Compounds for inhibiting c-myc/max/dna complex formation

ABSTRACT

Disclosed are novel compounds of specific chemical structures having inhibitory activity on c-Myc/Max/DNA complex formation or pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 15/663,179 filed on Jul. 28, 2017, which claimingthe benefit under 35 U.S.C. § 119 of the Korean Patent Application No.10-2016-0097429, filed on Jul. 29, 2016, and 10-2017-0093661 field onJul. 24, 2017, the disclosure of which is incorporated herein byreference in its entirety.

STATEMENT REGARDING GOVERNMENT RIGHTS

The present invention was undertaken with the support of 1) Developmentof pre-clinical and clinical candidates of c-Myc inhibitor No. 1511220grant funded by the National Cancer Center, 2) Development of c-Mycinhibitor for bladder cancer therapy No. 1510130 grant funded by theNational Cancer Center, 3) (Action Project) Development of pre-clinicaland clinical candidates of c-Myc inhibitor No. IK1506-H02 grant fundedby the Korea Research Institute of Chemical Technology, 4) (ActionProject) Development of pre-clinical and clinical candidates of c-Mycinhibitor No. IK1606-H02 grant funded by the Korea Research Institute ofChemical Technology and 5) (Action Project) Development of pre-clinicaland clinical candidates of c-Myc inhibitor No. IK1706H02 grant funded bythe Korea Research Institute of Chemical Technology.

BACKGROUND 1. Field of the Disclosure

The present disclosure relates to a group of novel compounds havinginhibitory activity on c-Myc/Max/DNA complex formation.

2. Discussion of Related Art

c-myc is a proto-oncogene encoding the c-Myc oncoprotein regulating celltransformation, growth, and differentiation, apoptosis, cell cycleprogression and the like. Myc family proteins including c-Myc form aheterodimer with the basic/helix-loop-helix/leucine zipper (bHLHZip)domain of Max protein, and the Myc/Max heterodimer binds to a specificDNA sequence (i.e., E-box motif). Heterodimer formation with Max proteinand subsequent DNA binding of the heterodimer are steps required fortranscriptional activation of c-Myc target genes, and play importantroles in promoting cell proliferation, malignant transformation,apoptosis and the like (see International Patent Publication No.WO2015/089180).

Abnormal expression of c-myc has been reported to be associated with avariety of cancers, including lung cancer, colorectal cancer, coloncancer, rectal cancer, breast cancer, bladder cancer, leukemia,myelogenous leukemia, lymphoma, small cell lung cancer, lung cancer,cervical carcinoma, osteosarcoma, glioblastoma, melanoma and the like(see Nature 1983 Nov. 10-16; 306(5939): 194-196; Cancer Res 1985 April;45(4): 1823-1827; and Mol. BioSyst., 2010, 6: 1503-1509). In addition,it has been reported that c-myc expression is elevated or deregulated invarious human cancers and is associated with tumors (Oncogene, 1999,18(19), 3004-16). Therefore, there has been much effort to developanti-cancer agents or anti-tumor agents by regulating c-myc expression.

However, in development of related drugs, development of substances thatdirectly inhibit c-Myc function has not been technically feasible, andthus most attempts have been made to indirectly regulate c-Myc function.However, such indirect c-Myc inhibitors may cause many unexpected sideeffects. In particular, since c-Myc plays an important role inregulating cellular activity in the body, serious side effects may occurwhen c-Myc inhibitors are not highly selective for c-Myc. In fact,development of many substances was discontinued due to toxicityproblems. For example, JQ1 has recently been reported to be useful formyeloma treatment by indirectly regulating c-Myc expression (see Cell.2011, 146(6): 904-917 and Blood. 2012, 120(14): 2843-2852), butdevelopment of JQ1 was discontinued due to serious side effects thereof.

Specifically, a motif responsible for binding of Myc and Max is theleucine zipper motif commonly found in general protein structures. Thus,certain proteins that bind to the leucine zipper motif inhibit Myc/Maxheterodimer formation, but have low selectivity.

In other words, when searching for a candidate substance, a substancethat binds to a unique motif present in a Myc/Max heterodimer should beselected and selectivity thereof should be confirmed, or side effectsmay be caused. For example, certain c-Myc inhibitors exhibit lowselectivity, inhibiting the activity of c-Jun/Fos transcription factorswith similar structures. Therefore, it is important to develop aninhibitor capable of selectively acting on a Myc/Max heterodimer. Inaddition, a targeting substance that inhibits formation of a complexbetween a c-Myc/Max dimer and DNA may have higher selectivity than atargeting substance that inhibits c-Myc/Max dimer formation.

Accordingly, it is necessary to develop an inhibitor capable of directlyinhibiting c-Myc action. Specifically, there is demand for thedevelopment of an inhibitor that has high selectivity for c-Myc and iscapable of inhibiting c-Myc activity, thus reducing side effects.

PRIOR ART DOCUMENTS Patent Documents

-   1. International Patent Publication No. WO 2014/071247 (disclosed on    May 8, 2014)-   2. International Patent Publication No. WO 2015/089180 (disclosed on    Jun. 18, 2014)

Non-Patent Documents

-   1. Steven Fletcher et al., Small-Molecule Inhibitors of the Myc    Oncoprotein, Biochimica et Biophysica Acta 1849 (2015) 525-543.-   2. Bing-Jia Chen et al., Small Molecules Targeting c-Myc Oncogene:    Promising Anti-Cancer Therapeutics, Int J Biol Sci 2014;    10(10):1084-1096.-   3. Kyung-Chae Jeong et al., Small-Molecule Inhibitors of c-Myc    Transcriptional Factor Suppress Proliferation and Induce Apoptosis    of Promyelocytic Leukemia Cell via Cell Cycle Arrest, Mol. BioSyst.,    2010, 6, 1503-1509.-   4. Ho Kyung Seo et al., Antitumor Activity of the c-Myc Inhibitor    KSI-3716 in Gemcitabine-Resistant Bladder Cancer, Oncotarget, 2014,    Vol. 5, No. 2: 326-337.

SUMMARY OF THE DISCLOSURE

Therefore, the present disclosure has been made in view of the aboveproblems, and it is an objective of the present disclosure to providenovel compounds having inhibitory activity on c-Myc/Max/DNA complexformation.

In accordance with the present disclosure, the above and otherobjectives can be accomplished by the provision of compounds having thestructures corresponding to Formula 1a or 1b below or pharmaceuticallyacceptable salts thereof:

in Formula 1,

R_(1a) to R_(1d) are each independently hydrogen, a halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀alkenyl, C₂₋₁₀ haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxylgroup, nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆alkanoyl, C₃₋₇ cycloalkyl, an aryl, a heterocycle, or a heteroaryl,wherein R_(1a) to R_(1d) may be each independently unsubstituted or oneor more hydrogens may be optionally substituted;

R₂ is hydrogen, C₁₋₆ alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀alkenyl carboxy, C₂₋₁₀ haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, ahydroxyl group, nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆alkylamino, C₁₋₆ cyanoalkyl, di(C₁₋₆ alkyl)amino, amino(C₁₋₆)alkyl,(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆ alkanoyl, C₃₋₇ cycloalkyl,(C₁₋₆)alkyl(C₃₋₇)cycloalkyl, aryl, (C₁₋₆)alkylaryl, (C₁₋₆)haloalkylaryl,(C₂₋₆)alkenylamide(C₁₋₆)alkylalkoxy, a heterocycle,(C₁₋₆)alkylheterocycle, a heteroaryl, or (C₁₋₆)alkylheteroaryl, whereinR₂ may be unsubstituted or optionally substituted;

R₃ is C₁₋₄ alkyl, isoalkyl, cycloalkyl, phenyl, or C₁₋₄ haloalkyl;

n is an integer from 0 to 2; and

Y is hydrogen, an alkyl, a haloalkyl, —C(O)alkyl, —C(O)aryl, asulfonylalkyl, a sulfonylaryl, an aryl, or an alkylaryl, wherein thealkyl has 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, and thearyl may be unsubstituted or one or more hydrogens may be optionallysubstituted.

In one embodiment, the present disclosure provides compoundscorresponding to Formula 2a or 2b below or pharmaceutically acceptablesalts thereof:

in Formula 2,

R_(1a) to R_(1d), R₃, n and Y are as defined in Formula 1;

m is an integer from 0 to 4; and

R₆ is phenyl, oxazole, pyrazole, pyrrole, imidazole, thiazole,thiophene, pyridine, pyrimidine, furan, indole, benzopyrazole,benzothiazole, benzooxazole, isoxazole, benzoimidazole,1,2,5-oxadiazole, pyrrolo[2,3-b]pyridine, or benzothiophene, which maybe unsubstituted or may be optionally substituted with one or more ofhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, halogen or may beoptionally substituted with one or more of hydrogen, phenyl, oxazole,pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine, pyrimidine,furan, indole, benzopyrazole, benzothiazole, benzooxazole, isoxazole,benzoimidazole, or benzothiophene or may be substituted withunsubstituted phenyl.

In one embodiment, the present disclosure provides compoundscorresponding to Formula 3a or 3b below or pharmaceutically acceptablesalts thereof:

in Formula 3,

R_(1a) to R_(1d), R₃, and n are as defined in Formula 1;

R_(4a) and R_(4b) are each independently hydrogen, a halogen, C₁₋₄alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkyl in which one or more hydrogens aresubstituted with substituents other than halogen;

Ar is phenyl, heteroaryl being 5-6-membered and having heteroatomsselected independently from N, S, or O, or biheteroaryl being8-12-membered and having heteroatoms selected independently from N, S,or O,

wherein Ar may be unsubstituted or may be optionally substituted withone or more of a halogen, C₁₋₆ alkyl, C₁₋₆ alkylthio, C₁₋₆ haloalkyl,C₁₋₆ haloalkylthio, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxyl group, COOH,nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkylamino, (C₁₋₆)alkylamino(C₁₋₆)alkylamino, C₁₋₆alkanoyl, SF₅, S(O)CF₃, SCF₃, NHC(═O)CH₃, C(═O)NHCH₃, NHSO2CH3, C₃₋₇cycloalkyl, an aryl, benzoyl, a heterocycle, a heteroaryl, phenyl,oxazole, pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine,pyrimidine, furan, indole, benzopyrazole, benzothiazole, benzooxazole,isoxazole, benzoimidazole, or benzothiophene,

wherein the substituents of Ar may be unsubstituted or may be optionallysubstituted with one or more of CF3, a halogen, (C₁₋₃)alkyl,(C₁₋₃)haloalkyl, hydrogen, COOH, nitro, cyano, amino, di(C1-3alkyl)amino, NHC(═O)CH3, or C(═O)NHCH3.

In accordance with an aspect of the present disclosure, the above andother objectives can be accomplished by the provision of a(pharmaceutical) composition including compounds according to Formula 1,2 or 3 or pharmaceutically acceptable salts thereof, and apharmaceutically acceptable carrier or additive.

In accordance with various aspects, the (pharmaceutical) composition mayfurther include one or more additional pharmaceutically active agents.

Novel compounds of the present disclosure having structures of Formula1, 2 or 3 or pharmaceutically acceptable salts thereof are useful forinhibiting c-Myc/Max/DNA complex formation, and thus may be useful fortreatment or prevention of cancers. Cancers, neoplasia, or tumors thatcan be treated by inhibiting c-Myc/Max/DNA complex formation include,for example, lung cancer (including small cell lung cancer and non-smallcell lung cancer), colorectal cancer, colon cancer, rectal cancer,breast cancer, prostate cancer, bladder cancer, myeloma, leukemia,myelogenous leukemia, lymphoma, cervical carcinoma, osteosarcoma,glioblastoma, melanoma, pancreatic cancer, gastric cancer, liver cancer,kidney cancer, gallbladder cancer, biliary tract cancer, and esophagealcancer.

Novel compounds according to the present disclosure and a(pharmaceutical) composition including the compounds are described indetail as follows.

The following description is merely illustrative and is not intended tolimit the present disclosure to specific application or uses.

As used herein, the following terms are defined as follows.

In the present specification, the terms “substituent”, “radical”,“group”, “moiety”, and “fragment” may be used interchangeably.

As used herein, the term “patient” refers to an animal (e.g., cow,horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig), preferably a mammal such as a primate (e.g., monkey orhuman), and most preferably a human.

As used herein, the term “alkyl”, when the number of carbon atoms is notparticularly limited, refers to a saturated straight or branchednon-cyclic hydrocarbon having 1 to 10 carbon atoms. The term “loweralkyl” refers to a straight or branched alkyl having 1 to 4 carbonatoms. Representative saturated straight alkyls include -methyl, -ethyl,-n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyland -n-decyl, whereas saturated branched alkyls include-isopropyl,-sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl,2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl,3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl,2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl,2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and3,3-diethylhexyl.

In the present specification, “C₁₋₆” means 1 to 6 carbon atoms. Forexample, C₁₋₆ alkyl means an alkyl having 1 to 6 carbon atoms.

As used herein, the term “alkenyl” refers to a saturated straight orbranched non-cyclic hydrocarbon having 2 to 10 carbon atoms andincluding at least one carbon-carbon double bond. Representativestraight and branched (C₂-C₁₀) alkenyls include -vinyl, -allyl,-1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl,-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl,-3-nonenyl, -1-decenyl, -2-decenyl, and -3-decenyl. These alkenyl groupsmay be optionally substituted. The term “cyclic alkylidene” is a ringhaving 3 to 8 carbon atoms and including at least one carbon-carbondouble bond, and the ring may have 1 to 3 heteroatoms.

As used herein, the term “alkynyl” refers to a straight or branchednon-cyclic hydrocarbon having 2 to 10 carbon atoms and including atleast one carbon-carbon triple bond. Representative straight or branched(C₂-C₁₀) alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonylyl, -2-nonylyl,-8-nonylyl, -1-decynyl, -2-decynyl, and -9-decynyl. These alkynyl groupsmay be optionally substituted.

As used herein, the terms “halogen” and “halo” refer to fluorine,chlorine, bromine or iodine.

As used herein, the term “haloalkyl”, “haloalkoxy”, “haloalkenyl” or“haloalkynyl” refers to an alkyl, alkoxy, alkenyl or alkynyl groupwherein one or more hydrogen atoms are substituted with halogen atoms,respectively. For example, haloalkyls include —CF₃, —CHF₂, —CH₂F, —CBr₃,—CHBr₂, —CH₂Br, —CCl₃, —CHCl₂, —CH₂CI, —CI₃, —CHI₂, —CH₂I, —CH₂—CF₃,—CH₂—CHF₂, —CH₂—CH₂F, —CH₂—CBr₃, —CH₂—CHBr₂, —CH₂—CH₂Br, —CH₂—CCl₃,—CH₂—CHCl₂, —CH₂—CH₂CI, —CH₂—CI₃, —CH₂—CHI₂, —CH₂—CH₂I, and the like.Here, the alkyl and the halogen are as defined above.

As used herein, the term “alkanoyl” or “acyl” refers to —C(O)alkylgroups including —C(O)CH₃, —C(O)CH₂CH₃, —C(O)(CH₂)₂CH₃, —C(O)(CH₂)₃CH₃,—C(O)(CH₂)₄CH₃, —C(O)(CH₂)₅CH₃, and the like, wherein the alkyl is asdefined above.

As used herein, the term “alkanoyloxy” or “acyloxy” refers to—OC(O)alkyl groups including —OC(O)CH₃, —OC(O)CH₂CH₃, —OC(O)(CH₂)₂CH₃,—OC(O)(CH₂)₃CH₃, —OC(O)(CH₂)₄CH₃, —OC(O)(CH₂)₅CH₃, and the like, whereinthe alkyl is as defined above.

As used herein, the term “alkoxy” refers to —O-(alkyl) including —OCH₃,—OCH₂CH₃, —O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —O(CH₂)₄CH₃, —O(CH₂)₅CH₃, and thelike, wherein the alkyl is as defined above.

As used herein, the term “lower alkoxy” refers to —O-(lower alkyl),wherein the lower alkyl is as defined above.

As used herein, the term “aryl” refers to a carbocyclic aromatic groupcontaining 5 to 10 cyclic atoms. Representative examples include phenyl,tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl,indenyl, azulenyl, and the like, without being limited thereto. Thecarbocyclic aromatic group may be optionally substituted.

The term “aryloxy” is RO—, wherein R is aryl as defined above. The term“arylthio” is RS—, wherein R is the aryl as defined above.

As used herein, the term “cycloalkyl” refers to a monocyclic orpolycyclic saturated ring having carbon and hydrogen atoms and nocarbon-carbon multiple bonds. For example, the cycloalkyl group includes(C₃-C₇)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl), without being limited thereto. Thecycloalkyl group may be optionally substituted. In one embodiment, thecycloalkyl group is a monocyclic or bicyclic ring.

As used herein, the term “mono-alkylamino” refers to —NH(alkyl)including —NHCH₃, —NHCH₂CH₃, —NH(CH₂)₂CH₃, —NH(CH₂)₃CH₃, —NH(CH₂)₄CH₃,—NH(CH₂)₅CH₃, and the like, wherein the alkyl is as defined above.

As used herein, the term “di-alkylamino” refers to N(alkyl)(alkyl)including —N(CH₃)₂, —N(CH₂CH₃)₂, —N((CH₂)₂CH₃)₂, —N(CH₃)(CH₂CH₃), andthe like, wherein each alkyl is alkyl as defined above.

As used herein, the term “alkylamino” is a concept that includesmono-alkylamino and di-alkylamino as defined above.

As used herein, the terms “carboxyl” and “carboxy” refer to —COOH.

As used herein, the term “aminoalkyl” refers to -(alkyl)-NH₂ including—CH₂—NH₂, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₄—NH₂, —(CH₂)₅—NH₂, and thelike, wherein the alkyl is as defined above.

As used herein, the term “mono-alkylaminoalkyl” refers to-(alkyl)-NH(alkyl) including —CH₂—NH—CH₃, —CH₂—NHCH₂CH₃,—CH₂—NH(CH₂)₂CH₃, —CH₂—NH(CH₂)₃CH₃, —CH₂—NH(CH₂)₄CH₃, —CH₂—NH(CH₂)₅CH₃,—(CH₂)₂—NH—CH₃, and the like, wherein each alkyl is alkyl as definedabove.

As used herein, “heteroaryl” is a 5- to 10-membered aromaticheterocyclic ring that has at least one heteroatom selected from thegroup consisting of nitrogen, oxygen, and sulfur and that includes amono- or bicyclic ring system and at least one carbon atom.Representative heteroaryls include triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl,morpholinyl, dioxanyl, tietanyl and oxazolyl.

As used herein, “heterocycle (heteroring)” refers to a saturated orunsaturated 5- to 7-membered monocyclic ring or a 7- to 10-memberedbicyclic/heterocyclic ring containing 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen and sulfur, wherein nitrogen and sulfurheteroatoms may be optionally oxidized, nitrogen heteroatoms may beoptionally quaternized, and a bicyclic ring in which a part of theheterocycle is fused to a benzene ring is included. The heterocycle maybe attached by heteroatoms or carbon atoms. The heterocycle includes theheteroaryl as defined above. Representative heterocycles includemorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, and tetrahydrothiopyranyl.

“Heterocycle fused to phenyl” refers to a heterocycle attached to twoadjacent carbon atoms of a phenyl ring, wherein the heterocycle is asdefined above.

As used herein, the term “hydroxyalkyl” refers to an alkyl in which oneor more hydrogen atoms are substituted with hydroxy and includes —CH₂OH,—CH₂CH₂OH, —(CH₂)₂CH₂OH, —(CH₂)₃CH₂OH, —(CH₂)₄CH₂OH, —(CH₂)₅CH₂OH,—CH(OH)—CH₃, —CH₂CH(OH)CH₃, and the like, wherein the alkyl is asdefined above.

As used herein, the term “sulfonyl” refers to —SO₃H.

As used herein, the term “sulfonylalkyl” refers to —SO₂-(alkyl)including —SO₂—CH₃, —SO₂—CH₂CH₃, —SO₂—(CH₂)₂CH₃, —SO₂—(CH₂)₃CH₃,—SO₂—(CH₂)₄CH₃, and —SO₂—(CH₂)₅CH₃, wherein the alkyl is as definedabove.

As used herein, the term “sulfinylalkyl” refers to —SO-(alkyl) including—SO—CH₃, —SO—CH₂CH₃, —SO—(CH₂)₂CH₃, —SO—(CH₂)₃CH₃, —SO—(CH₂)₄CH₃,—SO—(CH₂)₅CH₃, and the like, wherein the alkyl is as defined above.

“Thioalkyl” includes —S—CH₃, —S—CH₂CH₃, —S—(CH₂)₂CH₃, —S—(CH₂)₃CH₃,—S—(CH₂)₄CH₃, —S—(CH₂)₅CH₃, and the like, wherein the alkyl is asdefined above.

As used herein, the term “substituted” indicates that the hydrogen atomof the moiety (e.g., alkyl, aryl, heteroaryl, heterocycle or cycloalkyl)to be replaced is replaced with a substituent. In one embodiment, eachcarbon atom of the substituted group is not substituted with two or moresubstituents. In another embodiment, each carbon atom of the substitutedgroup is not substituted with one or more substituents. In the case of aketo substituent, two hydrogen atoms are substituted with oxygenattached to carbon by a double bond.

Unless otherwise specified with respect to a substituent, a halogen,hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl,heterocycle, —NO₂, —NR_(a)R_(b), —NR_(a)C(═O)R_(b),—NR_(a)C(═O)NR_(a)R_(b), —NR_(a)C(═O)OR_(b), —NR_(a)SO₂R_(b), —OR_(a),—CN, —C(═O)R_(a), —C(═O)OR_(a), —C(═O)NR_(a)R_(b), —OC(═O)R_(a),—OC(═O)OR_(a), —OC(═O)NR_(a)R_(b), —NR_(a)SO₂R_(b), —PO₃R_(a),—PO(OR_(a))(OR_(b)), —SO₂R_(a), —S(O)R_(a), —SO(NR_(a))R_(b) (e.g.,sulfoximine), —S(NR_(a))R_(b) (e.g., sulfilimine) and —SR_(a) may beused as substituents in the present disclosure, wherein R_(a) and R_(b)are the same or different and are each independently hydrogen, ahalogen, amino, an alkyl, an alkoxyalkyl, a haloalkyl, aryl or aheterocycle, or may be in the form of a heterocycle containing attachednitrogen atoms. Here, R_(a) and R_(b) may be plural depending on thebonded atom.

As used herein, “basic structure of quinoline” refers to the followingstructure.

According to the present disclosure, “pharmaceutically acceptable salts”include salts of active compounds prepared from relatively non-toxicacids and bases depending on particular substituents found in thecompounds described herein. When the compounds of the present disclosureinclude relatively acidic functionality, base addition salts may beobtained by bringing the neutral forms of the compounds into contactwith a sufficient amount of a desired base in a pure or suitable inertsolvent. For example, pharmaceutically acceptable base addition saltsinclude sodium, potassium, calcium, ammonium, organic amino or magnesiumsalts or similar salts. When the compounds of the present disclosureinclude relatively basic functionality, acid addition salts may beobtained by bringing the neutral forms of the compounds into contactwith a sufficient amount of a desired acid in a pure or suitable inertsolvent. For example, pharmaceutically acceptable acid addition saltsinclude salts derived from relatively non-toxic organic acids includingacetic acid, propionic acid, isobutylic acid, oxalic acid, maleic acid,malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid,mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonicacid, citric acid, tartaric acid, methanesulfonic acid, and analogsthereof. In addition, the pharmaceutically acceptable acid additionsalts include hydrogen chloride, hydrogen bromide, nitric acid, carbonicacid, monohydrogen carbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogen phosphoric acid, sulfuric acid,monohydrogensulfuric acid, hydrogen iodide or phosphorous acid andanalogs thereof. In addition, the pharmaceutically acceptable acidaddition salts include salts of amino acids such as arginate and analogsthereof and analogs of organic acids such as glucuronic or galacturonicacids and analogs thereof (e.g., Berge et al. (1977) J. Pharm. Sci. 66:1-19). Certain compounds of the present disclosure have both basic andacidic functionalities to convert the compounds into base or acidaddition salts. Other examples of salts are disclosed in documents(e.g., Remington's Pharmaceutical Sciences, 18^(th) eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19^(th) eds., Mack Publishing, Easton Pa. (1995)) known in theart to which the present disclosure pertains.

As used herein, “effective dose” refers to an amount of the compounds ofthe present disclosure sufficient to destroy, modify, control oreliminate primary, localized or metastatic cancer cells or cancertissues; to slow or minimize the spread of cancer; or to providetherapeutic benefits in treatment or management of cancer, neoplasticdiseases, or tumors. In addition, “effective dose” refers to an amountof the compounds of the present disclosure sufficient to cause the deathof neoplastic cells including cancer cells. In addition, “effectivedose” refers to an amount of the compounds sufficient to inhibit orreduce c-Myc/Max/DNA complex formation either in vitro or in vivo.

As used herein, “inhibition of c-Myc/Max/DNA complex formation”indicates that, when compared to cells that are not exposed to thecompounds of the present disclosure, the amount of c-Myc/Max/DNAcomplexes is decreased or the degree of binding of the c-Myc/Maxheterodimer to DNA is suppressed or delayed in cells exposed to thecompounds of the present disclosure.

As used herein, “preventive effective dose” refers to an amount of thecompounds of the present disclosure sufficient to inhibit cancerdevelopment in patients susceptible to the recurrence, or spread ofcancer, susceptible to cancer or patients previously exposed to acarcinogen. At this time, the type of patient is not limited thereto.

As used herein, the term “neoplastic” refers to an abnormal growth ofcells or tissues (e.g., a boil) that may be benign or cancerous.

As used herein, “prevention” refers to preventing the recurrence, spreador onset of cancer in a patient.

As used herein, “treatment” includes eradication, removal, modification,or control of primary, localized or metastatic cancer tissues; andrefers to minimizing or delaying the spread of cancer.

As used herein, the term “the compounds of the present disclosure”refers to compounds corresponding to each of Formula 1 (1a and 1b),Formula 2 (2a and 2b) and Formula 3 (3a and 3b), and also includesclathrates, hydrates, solvates, or polymorphs thereof. In addition, theterm “the compounds of the present disclosure” also includespharmaceutically acceptable salts of the compounds of the presentdisclosure, when pharmaceutically acceptable salts thereof are notmentioned. According to one embodiment, the compounds of the presentdisclosure may be present as stereomerically pure compounds (e.g.,compounds that are substantially free of other stereoisomers (e.g., 85%ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee ormore)). That is, in addition to the compounds corresponding to Formula1, 2 or 3, when the salts of the compounds are tautomeric isomers and/orstereoisomers (e.g., geometrical isomers and conformational isomers),isolated isomers thereof and respective mixtures thereof are within thescope of the compounds of the present disclosure. When the compounds ofthe present disclosure or salts thereof have asymmetric carbons in thestructure thereof, optically active compounds and racemic mixturesthereof are also within the scope of the compounds of the presentdisclosure. For example, as shown in the following scheme, when thecompounds of the present disclosure have a sulfoxide (SOR) structure,the compounds may have chirality. The R and S forms of these isomers areincluded in the category of the compounds of the present disclosure, andthe mixtures of the R and S forms are also included in the category ofthe compounds of the present disclosure.

In addition, as shown in Scheme 1, the compounds of the presentdisclosure may exist in either keto or enol form, both of which areincluded in the category of the compounds of the present disclosure.

When used herein, the term “polymorph” refers to solid crystalline formsof the compounds of the present disclosure or complexes thereof.Different polymorphs of the same compound exhibit different physical,chemical and/or spectral characteristics. Differences in physicalcharacteristics include stability (e.g., heat or light stability),compressibility and density (important for formulation and productproduction), and dissolution rate (which may affect bioavailability),without being limited thereto. Differences in stability cause changes inchemical reactivity (e.g., differential oxidation, as evidenced by morerapid color change when composed of one polymorph than when composed ofanother polymorph) or mechanical characteristics (e.g., as dynamicallypreferred polymorphs, stored tablet fragments are converted into morethermodynamically stable polymorphs), or both (tablets of one polymorphare more sensitive to degradation at high humidity). Other physicalproperties of polymorphs may affect processing thereof. For example, onepolymorph may be more likely to form solvent compounds than anotherpolymorph, e.g., due to a shape or particle size distribution thereof,or may be more difficult to filter or wash than another polymorph

As used herein, the term “solvent compounds” refers to the compounds ofthe present disclosure or pharmaceutically acceptable salts thereof,including a stoichiometric or non-stoichiometric amount of a solventbound by force between non-covalent molecules. Preferred solvents arevolatile and non-toxic, and may be administered to humans in very smalldoses.

As used herein, the term “hydrates” refers to the compounds of thepresent disclosure or pharmaceutically acceptable salts thereof,including a stoichiometric or non-stoichiometric amount of water boundby force between non-covalent molecules.

As used herein, the term “clathrates” refers to the compounds of thepresent disclosure or salts thereof in the form of a crystal latticeincluding a space (e.g., channel) in which guest molecules (e.g.,solvent or water) are confined.

When any compounds (prodrugs) isolated from the body are capable ofproducing the compounds of the present disclosure or salts thereof, suchcompounds are also within the scope of the present disclosure. As usedherein, and unless otherwise indicated, the term “prodrugs” refer to thecompounds of the present disclosure that are capable of undergoinghydrolysis, oxidation, or other reactions under biological conditions(in vitro or in vivo) to provide active compounds, particularly thecompounds of the present disclosure. For example, prodrugs includebiohydrolyzable compounds that are biodegraded to yield the compounds ofthe present disclosure, including biohydrolyzable portions such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogs, without being limited thereto.Preferably, prodrugs of compounds having a carboxyl group are loweralkyl esters of carboxylic acids. Carboxylic esters are typically formedby esterifying a portion of carboxylic acids present in the molecule.Prodrugs may be readily prepared using well known methods as describedin the following documents: Burger's Medicinal Chemistry and DrugDiscovery 6^(th) ed. (Donald J. Abrahamed., 2001, Wiley) and Design andApplication of Prodrugs (H. Bundgaard ed., 1985, Harwood AcademicPublishers Gmfh).

As used herein, the term “purified” indicates that when a substance isseparated, the purity of the substance is at least 90%. The purity ofthe substance may be at least 95% in one embodiment, 99% in anotherembodiment, and 99.9% in still another embodiment.

The term “hydrido” refers to a single —H atom (H), and may beinterchanged with the symbol “H” or the term “hydrogen”.

When substituents are described as being “optionally substituted”, thesubstituents may be unsubstituted (1) or may be substituted with atleast one of substituents as defined (2). When a substitutable positionis not substituted, a default substituent is a hydrido radical.

As used herein, the singular forms “a” and “an” may include the pluralforms unless context clearly dictates otherwise.

The term “pharmaceutically acceptable” means suitable for use as apharmaceutical preparation and is generally considered to be safe forsuch use. In addition, pharmaceutically acceptable substances refer tosubstances which have been formally approved by the governing body ofthe State for such use or which are on the list of Korean Pharmacopoeiaor US Pharmacopoeia.

Compounds of the Present Disclosure

The present disclosure provides compounds having the structurescorresponding to Formula 1 (1a or 1b) below or pharmaceuticallyacceptable salts thereof:

in Formula 1,

R_(1a) to R_(1d) are each independently hydrogen, a halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀alkenyl, C₂₋₁₀ haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxylgroup, nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆alkanoyl, C₃₋₇ cycloalkyl, an aryl, a heterocycle, or a heteroaryl,wherein R_(1a) to R_(1d) may be each independently unsubstituted oroptionally substituted;

R₂ is hydrogen, C₁₋₆ alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀alkenyl carboxy, C₂₋₁₀ haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, ahydroxyl group, nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆alkylamino, C₁₋₆cyanoalkyl, di(C₁₋₆ alkyl)amino, amino(C₁₋₆)alkyl,(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆ alkanoyl, C₃₋₇ cycloalkyl,(C₁₋₆)alkyl(C₃₋₇)cycloalkyl, an aryl, (C₁₋₆)alkylaryl,(C₁₋₆)haloalkylaryl, (C₂₋₆)alkenylamide(C₁₋₆)alkylalkoxy, a heterocycle,(C₁₋₆)alkylheterocycle, a heteroaryl, or (C₁₋₆)alkylheteroaryl, whereinR₂ may be unsubstituted or optionally substituted;

R₃ is C₁₋₄ alkyl, isoalkyl, cycloalkyl, phenyl, or C₁₋₄ haloalkyl;

n is an integer from 0 to 2; and

Y is hydrogen, an alkyl, a haloalkyl, —C(O)alkyl, —C(O)aryl, asulfonylalkyl, a sulfonylaryl, an aryl, or an alkylaryl, wherein analkyl has 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, and anaryl may be unsubstituted or optionally substituted.

In another embodiment, the present disclosure provides compounds havingthe structures of Formula 2 (2a or 2b) or pharmaceutically acceptablesalts thereof:

in Formula 2,

R_(1a) to R_(1d), R₃, n and Y are as defined in Formula 1;

m is an integer from 0 to 4; and

R₆ is phenyl, oxazole, pyrazole, pyrrole, imidazole, thiazole,thiophene, pyridine, pyrimidine, furan, indole, benzopyrazole,benzothiazole, benzooxazole, isoxazole, benzoimidazole,1,2,5-oxadiazole, pyrrolo[2,3-b]pyridine, or benzothiophene, which maybe unsubstituted or may be optionally substituted with one or more ofhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, a halogen or may beoptionally substituted with one or more of hydrogen, phenyl, oxazole,pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine, pyrimidine,furan, indole, benzopyrazole, benzothiazole, benzooxazole, isoxazole,benzoimidazole, or benzothiophene or may be substituted withunsubstituted phenyl.

In another embodiment, the present disclosure provides compounds havingthe structures corresponding to Formula 3a or 3b or pharmaceuticallyacceptable salts thereof:

in Formula 3,

R_(1a) to R_(1d), R₃, and n are as defined in Formula 1;

R_(4a) and R_(4b) are each independently hydrogen, a halogen, C₁₋₄alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkyl in which one or more hydrogens aresubstituted with substituents other than halogen;

Ar is phenyl, heteroaryl being 5-6-membered and having heteroatomsselected independently from N, S, or O, or biheteroaryl being8-12-membered and having heteroatoms selected independently from N, S,or O,

wherein Ar may be unsubstituted or may be optionally substituted withone or more of a halogen, C₁₋₆ alkyl, C₁₋₆ alkylthio, C₁₋₆ haloalkyl,C₁₋₆ haloalkylthio, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxyl group, COOH,nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkylamino, (C₁₋₆)alkylamino(C₁₋₆) alkylamino, C₁₋₆alkanoyl, SF₅, S(O)CF₃, SCF₃, NHC(═O)CH₃, C(═O)NHCH₃, NHSO2CH3, C₃₋₇cycloalkyl, an aryl, benzoyl, a heterocycle, a heteroaryl, phenyl,oxazole, pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine,pyrimidine, furan, indole, benzopyrazole, benzothiazole, benzooxazole,isoxazole, benzoimidazole, or benzothiophene,

wherein the substituents of Ar may be unsubstituted or may be optionallysubstituted with one or more of CF3, a halogen, (C₁₋₃)alkyl,(C₁₋₃)haloalkyl, hydrogen, COOH, nitro, cyano, amino, di(C1-3alkyl)amino, NHC(═O)CH3, or C(═O)NHCH3.

To obtain novel compounds having high inhibitory activity onc-Myc/Max/DNA complex formation, having high selectivity toc-Myc/Max/DNA complexes, and consequently having an inhibitory effect oncancer cells while having minimal side effects, the present inventorssynthesized various compounds and performed various experiments toevaluate the compounds. As a result, the present inventors completed thepresent disclosure by confirming that the novel compounds of the presentdisclosure were suitable for the above-described various objects.

For example, a compound having a substituent linked to —S— at the2-position of the basic structure of quinoline is superior in safety toa compound having a substituent linked to —NH—. Specifically, in thecase of the compound having a substituent linked to —NH—, the compoundis somewhat superior but has very severe cardiotoxicity. For example, inthe case of a mouse xenograft model experiment using compound KSI-3716of the following Formula 4, all of the experimental group (30 mpk,intraperitoneal administration (IP)) died. On the other hand, when thecompounds of the present disclosure (e.g., Compound 4) were subjected toIV and IP single toxicity tests using 40 mpk, there were no deaths, nosignificant weight changes, and no abnormal symptoms in terms of generalsymptoms such as feed intake and drinking water intake.

TABLE 1 Single toxicity evaluation results of Compound 4 according tothe present disclosure Species Sex Dose Percentage Mouse Male IV 40mg/kg 0 (0/2) Mouse Male IP 40 mg/kg 0 (0/2) Mouse Female IV 40 mg/kg 0(0/2) Mouse Female IP 40 mg/kg 0 (0/2)

-   -   No deaths were observed in single-dose administration of 40 mpk.    -   General symptoms: Feeding and drinking were good, and no other        abnormal symptoms were observed.    -   Weight changes: In general, weight gain was observed, but weight        gain was slightly reduced in certain individuals.    -   In the case of KSI-3716, all animals died at 30 mpk (IP).

In addition, in cardiotoxicity experiments using zebrafish, allzebrafish (n=10) died when 5 μM of a compound (e.g., KSI-3716 of Formula4) having a substituent linked to —NH— was used. On the other hand, whenthe compounds of the present disclosure were used, lethality was verylow and the compounds did not cause changes in heart rate. Theexperimental results of representative compounds are shown in thefollowing Table 2.

TABLE 2 Changes in heart rate depending on treatment of compounds inzebrafish (mean, n = 10) Changes in heart Compounds rate (%) LethalityNote 10 μM Astemizole 46.2 0/10 5 μM of KSI-3716 — 10/10  Not measurableby death of all zebrafish 5 μM of Compound 4 88.5 1/10 5 μM of Compound33 97.3 0/10 No significant heart rate inhibition

In another example, R₂ linked to S at the 2-position of the basicstructure of quinoline is preferably a phenyl structure in view of thevarious objects of the present disclosure. In addition, from theviewpoint of activity, it is preferable that the phenyl group is linkedvia —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂— as a bridge ratherthan directly linked to S. More preferably, —CH₂— or —CH₂CH₂— is used asa bridge.

For example, in view of activity, one or more of R_(1a) to R_(1d) arepreferably substituted with substituents, more preferably halogens. Inparticular, when R_(1a) and R_(1d) were simultaneously substituted withhalogens, even better activity was observed.

In the case of R₃, C₁₋₄ alkyl, isoalkyl, cycloalkyl, phenyl, or C₁₋₄haloalkyl exhibited excellent activity. In particular, groups such asmethyl or halomethyl exhibited better activity. In addition, when R₃ was—CF₃, metabolic stability was increased. On the other hand, when R₃ washeteroatoms of O or N, the activity desired in the present disclosurewas weak.

In view of the various objects of the present disclosure, Y ispreferably hydrogen.

R₄ (R_(4a) and/or R_(4b)) is an important site for metabolic stability,and is preferably a lower alkyl or halogen for various objects of thepresent disclosure.

Non-limiting examples of the compounds according to the presentdisclosure include the compounds of Table 3 below and pharmaceuticallyacceptable salts thereof.

TABLE 3 Compound Number Structure IUPAC Name 1

3-acetyl-8-bromo-5-chloro-2- (methylsulfinyl)quinolin-4(1H)-one 2

3-acetyl-8-bromo-5-chloro-2- (methylthio)quinolin-4(1H)-one 3

3-acetyl-2-(benzylthio)-8-bromo-5- chloroquinolin-4(1H)-one 4

3-acetyl-2-(benzylsulfinyl)-8-bromo-5- chloroquinolin-4(1H)-one 5

3-acetyl-8-bromo-5-chloro-1-methyl-2- (methylthio)quinolin-4(1H)-one 6

3-acetyl-5,8-dichloro-2- (methylsulfinyl)quinolin-4(1H)-one 7

3-acetyl-6-fluoro-1-methyl-2- (methylthio)quinolin-4(1H)-one 8

1-(6-fluoro-4-hydroxy-2-(methylthio)quinolin- 3-yl)ethan-1-one 9

3-acetyl-8-bromo-1-(4-bromobenzoyl)-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one 10

3-acetyl-8-bromo-5-chloro-2-((4- chlorobenzyl)thio)quinolin-4(1H)-one 11

3-acetyl-8-bromo-5-chloro-2-((4-chlorobenzyl)sulfinyl)quinolin-4(1H)-one 12

3-acetyl-8-bromo-5-chloro-2- (phenylthio)quinolin-4(1H)-one 13

3-acetyl-8-bromo-5-chloro-2- (phenylsulfinyl)quinolin-4(1H)-one 14

3-acetyl-8-bromo-5-chloro-2-((2- methoxyphenyl)thio)quinolin-4(1H)-one15

3-acetyl-8-bromo-5-chloro-2-((2-methoxyphenyl)sulfinyl)quinolin-4(1H)-one 16

3-acetyl-8-bromo-2-((4-bromophenyl)thio)-5- chloroquinolin-4(1H)-one 17

3-acetyl-8-bromo-2-((4-bromophenyl)sulfinyl)- 5-chloroquinolin-4(1H)-one18

1,1′-(8-bromo-5-chloro-2-(methylthio)-4-oxoquinoline-1,3(4H)-diyl)bis(ethan-1-one) 19

1,1′-(8-bromo-5-chloro-2-(methylsulfinyl)-4-oxoquinoline-1,3(4H)-diyl)bis(ethan-1-one) 20

3-acetyl-2-(benzylsulfinyl)-8-bromo-1-(4-bromobenzoyl)-5-chloroquinolin-4(1H)-one 21

3-acetyl-8-bromo-1-(4-bromobenzoyl)-5-chloro-2-(methylsulfonyl)quinolin-4(1H)-one 22

3-acetyl-8-bromo-5-chloro-1-(3-chloro-4-fluorobenzyl)-2-(methylsulfinyl)quinolin-4(1H)- one 23

3-acetyl-2-(benzylthio)-8-bromo-1-(4-bromobenzoyl)-5-chloroquinolin-4(1H)-one 24

3-acetyl-8-bromo-5-chloro-2- (isopropylthio)quinolin-4(1H)-one 25

3-acetyl-8-bromo-5-chloro-2- (isopropylsulfinyl)quinolin-4(1H)-one 26

3-acetyl-8-bromo-5-chloro-2-((1- phenylethyl)sulfinyl)quinolin-4(1H)-one27

3-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)methyl)benzonitrile 28

3-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4- dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile 29

3-acetyl-8-bromo-5-chloro-2-((2,4-difluorobenzyl)sulfinyl)quinolin-4(1H)-one 30

3-acetyl-8-bromo-5-chloro-2-((3-chloro-4-fluorobenzyl)thio)quinolin-4(1H)-one 31

3-acetyl-8-bromo-5-chloro-2-((3-chloro-4-fluorobenzyl)sulfinyl)quinolin-4(1H)-one 32

3-acetyl-8-bromo-5-chloro-2-((4- nitrobenzyl)thio)quinolin-4(1H)-one 33

3-acetyl-8-bromo-5-chloro-2-((4- nitrobenzyl)sulfinyl)quinolin-4(1H)-one34

3-acetyl-2-(benzylsulfonyl)-8-bromo-5- chloroquinolin-4(1H)-one 35

3-acetyl-8-bromo-5-chloro-1-(methylsulfonyl)-2-(methylthio)quinolin-4(1H)-one 36

3-acetyl-8-bromo-5-chloro-2-(methylsulfinyl)-1-((trifluoromethyl)sulfonyl)quinolin-4(1H)-one 37

3-acetyl-8-bromo-5-chloro-1-((4-chlorophenyl)sulfonyl)-2-(methylthio)quinolin- 4(1H)-one 38

3-acetyl-8-bromo-5-chloro-2-(methylthio)-1-((4-nitrophenyl)sulfonyl)quinolin-4(1H)-one 39

3-acetyl-8-bromo-5-chloro-1-(ethylsulfonyl)-2-(methylsulfinyl)quinolin-4(1H)-one 40

3-acetyl-8-bromo-1-((4-(tert- butyl)phenyl)sulfonyl)-5-chloro-2-(methylthio)quinolin-4(1H)-one 41

3-acetyl-8-bromo-1-((4-(tert- butyl)phenyl)sulfonyl)-5-chloro-2-(methylsulfonyl)quinolin-4(1H)-one 42

3-acetyl-8-bromo-1-((4-(tert- butyl)phenyl)sulfonyl)-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one 43

3-acetyl-8-bromo-5-chloro-2-((2,5-dichlorobenzyl)thio)quinolin-4(1H)-one 44

3-acetyl-8-bromo-5-chloro-2-((2,5-dichlorobenzyl)sulfinyl)quinolin-4(1H)-one 45

3-acetyl-8-bromo-5-chloro-2-((3,5-difluorobenzyl)thio)quinolin-4(1H)-one 46

3-acetyl-8-bromo-5-chloro-2-((3,5-difluorobenzyl)sulfinyl)quinolin-4(1H)-one 47

3-acetyl-8-bromo-5-chloro-2-((3- iodobenzyl)thio)quinolin-4(1H)-one 48

3-acetyl-8-bromo-5-chloro-2-((3- iodobenzyl)sulfinyl)quinolin-4(1H)-one49

3-acetyl-8-bromo-5-chloro-2-((3- fluorobenzyl)thio)quinolin-4(1H)-one 50

3-acetyl-8-bromo-5-chloro-2-((3-fluorobenzyl)sulfinyl)quinolin-4(1H)-one 51

3-acetyl-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin- 4(1H)-one 52

1-(2-(benzylthio)-8-bromo-5-chloro-4- hydroxyquinolin-3-yl)ethan-1-one53

1-(2-(benzylsulfinyl)-8-bromo-5-chloro-4-hydroxyquinolin-3-yl)ethan-1-one 54

1-(2-(benzylsulfonyl)-8-bromo-5-chloro-4-hydroxyquinolin-3-yl)ethan-1-one 55

3-acetyl-8-bromo-5-chloro-2-((3-methoxybenzyl)sulfinyl)quinolin-4(1H)-one 56

3-acetyl-8-bromo-5-chloro-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin- 4(1H)-one 57

3-acetyl-5,8-dichloro-2-((4- nitrobenzyl)sulfinyl)quinolin-4(1H)-one 58

2-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4- dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile 59

3-acetyl-8-bromo-5-chloro-2-((3,5-dimethoxybenzyl)sulfinyl)quinolin-4(1H)-one 60

3-acetyl-8-bromo-2-((4-(tert-butyl)benzyl)sulfinyl)-5-chloroquinolin-4(1H)- one 61

3-acetyl-8-bromo-5-chloro-2- ((methoxymethyl)thio)quinolin-4(1H)-one 62

3-acetyl-8-bromo-5-chloro-2-mercaptoquinolin- 4(1H)-one 63

3-acetyl-2-((4-benzoylbenzyl)sulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one 64

3-acetyl-8-bromo-5-chloro-2-((4-((trifluoromethyl)sulfinyl)benzyl)sulfinyl)quinolin- 4(1H)-one 65

2-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)acetonitrile 66

2-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)acetonitrile 67

(Z)-3-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)acrylic acid 68

3-acetyl-8-bromo-5-chloro-2-((4-(pentafluoro-l6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 69

3-acetyl-8-bromo-5-chloro-2-((2-fluoro-4- (pentafluoro-l6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 70

3-acetyl-8-bromo-5-chloro-2-((4-(trifluoromethyl)benzyl)sulfinyl)quinolin- 4(1H)-one 71

3-acetyl-8-bromo-5-chloro-2-((4-(trifluoromethoxy)benzyl)sulfinyl)quinolin- 4(1H)-one 72

3-acetyl-8-bromo-5-chloro-2-(((5- (trifluoromethyl)furan-2-yl)methyl)sulfinyl)quinolin-4(1H)-one 73

4-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4- dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile 74

3-acetyl-8-bromo-5-chloro-2-((2-chloro-6-fluorobenzyl)sulfinyl)quinolin-4(1H)-one 75

3-acetyl-8-bromo-5-chloro-2-((2-methoxy-4- (pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 76

3-acetyl-8-bromo-5-chloro-2-((3-fluoro-5- (pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 77

3-acetyl-8-bromo-5-chloro-2-((3-(pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 78

3-acetyl-8-bromo-5-chloro-2-(((perfluorophenyl)methyl)sulfinyl)quinolin- 4(1H)-one 79

3-acetyl-5,8-dichloro-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin- 4(1H)-one 80

3-acetyl-5,8-difluoro-2-((4-(pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 81

3-acetyl-5,8-difluoro-2-(((5- (trifluoromethyl)furan-2-yl)methyl)sulfinyl)quinolin-4(1H)-one 82

3-acetyl-5,8-difluoro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 83

3-acetyl-5,8-dichloro-2-((4- iodobenzyl)sulfinyl)quinolin-4(1H)-one 84

3-acetyl-8-bromo-5-chloro-2-((pyridin-3-ylmethyl)sulfinyl)quinolin-4(1H)-one 85

5,8-difluoro-3-isobutyryl-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin- 4(1H)-one 86

5,8-dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin- 4(1H)-one 87

3-benzoyl-5,8-difluoro-2-((4-(pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 88

3-benzoyl-5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 89

methyl 5-(((3-acetyl-5,8-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)furan-2- carboxylate 90

2-(((3-acetyl-5,8-dichloro-4-oxo-1,4- dihydroquinolin-2-yl)sulfinyl)methyl)isoindoline-1,3-dione 91

methyl 4-(((3-acetyl-5,8-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)benzoate 92

3-acetyl-5-methoxy-2-((4-(pentafluoro-λ6-sulfanyl)benzyl)thio)quinolin-4(1H)-one 93

3-acetyl-5-methoxy-2-((4-(pentafluoro-λ6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one 94

3-acetyl-5-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 95

8-bromo-5-chloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin- 4(1H)-one 96

8-bromo-5-chloro-3-(cyclopropanecarbonyl)-2- (((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 97

5,8-dichloro-3-(cyclopropanecarbonyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin- 4(1H)-one 98

5-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)thiophene- 2-carbonitrile 99

2-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)sulfinyl)-3-acetyl-8-bromo-5- chloroquinolin-4(1H)-one 100

3-acetyl-2-(((6-aminopyridin-3-yl)methyl)sulfinyl)-8-bromo-5-chloroquinolin- 4(1H)-one 101

8-bromo-5-chloro-3-(cyclopropanecarbonyl)-2- ((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin- 4(1H)-one 102

3-acetyl-8-bromo-5-chloro-2-(((2-methyl-6- (trifluoromethyl)pyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 103

N-(4-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4- dihydroquinolin-2-yl)sulfinyl)methyl)phenyl)methanesulfonamide 104

3-acetyl-8-bromo-5-chloro-2-(((6-chloropyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 105

3-acetyl-8-bromo-5-chloro-2-(((6-((2- methoxyethyl)amino)pyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one 106

3-acetyl-8-bromo-5-chloro-2-(((4-methyl-1,2,5-oxadiazol-3-yl)methyl)sulfinyl)quinolin-4(1H)- one 107

2-(((1H-pyrrolo[2,3-b]pyridin-5- yl)methyl)sulfinyl)-3-acetyl-8-bromo-5-chloroquinolin-4(1H)-one

In another embodiment, the present disclosure provides therapeuticallyeffective amounts of the compounds of Formula 1, 2 or 3 orpharmaceutically acceptable salts thereof, and a (pharmaceutical)composition including a pharmaceutically acceptable carrier.

In another embodiment, the present disclosure provides therapeuticallyeffective amounts of the compounds of Formula 1, 2 or 3 orpharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier, and provides a (pharmaceutical) compositionincluding a therapeutically effective amount of an active pharmaceuticalingredient selected from the group consisting of other anti-canceragents other than the compounds of the present disclosure, cytostaticdrugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers andcell adhesion molecule inhibitors.

When the novel compounds according to the present disclosure are used asanti-cancer agents, the dose is as follows. Any suitable route foradministration of the compounds of the present disclosure may beselected, the type of pharmaceutical composition suitable for such routemay be determined, and for the intended treatment, the compound may beadministered in an effective dose. The effective dose is generally fromabout 0.001 to about 100 mg/kg body weight/day, preferably from about0.01 to about 30 mg/kg/day, in a single or divided dose. Depending onthe age, species, and diseases or conditions to be treated, a dose belowthe lower limit of this range may be appropriate. In other cases, higherdoses may be used without harmful side effects. Higher doses may bedivided into smaller doses and administered daily. Methods ofdetermining an appropriate dose are well known in the art to which thepresent disclosure pertains. For example, a document, such as Remington:The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed.,2000, may be used.

References for Preparing (Pharmaceutical) Composition

Methods for the preparation of pharmaceutical compositions for thetreatment or prevention of diseases or conditions are well known tothose of ordinary skill in the art. For example, as described inreferences such as Handbook of Pharmaceutical Excipients (7^(th) ed.),Remington: The Science and Practice of Pharmacy (20^(th) ed.),Encyclopedia of Pharmaceutical Technology (3^(rd) ed.) Sustained andControlled Release Drug Delivery Systems (1978), a pharmaceuticallyacceptable carrier, additives and the like may be suitably mixed withthe compounds according to the present disclosure to prepare apharmaceutical composition for the object of the present disclosure.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Hereinafter, the present disclosure is described in detail withreference to the following examples. However, the examples according tothe present disclosure can be modified into various other forms, and thescope of the present disclosure should not be construed as being limitedto the following examples. The examples are provided to more fullyexplain the present disclosure to those skilled in the art to which thepresent disclosure pertains.

Preparation of Compounds of the Present Disclosure

The reagents and solvents used in the experiments described below can bepurchased from Aldrich Chemical Co. (Milwaukee, Wis., USA). A ¹H-NMRspectrum was measured using a Varian Gemini 400 MHz NMR spectrometer.

Preparation of Compounds3-acetyl-8-bromo-5-chloro-2-(methylthio)quinolin-4(1H)-one (4a),3-acetyl-2-(benzylthio)-8-bromo-5-chloroquinolin-4(1H)-one (4b),3-acetyl-8-bromo-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one (5a), and3-acetyl-2-(benzylsulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one (5b)

Synthesis of 2-bromo-5-chlorophenyl Isothiocyanate (2) (IsothiocyanateFormation)

2-Bromo-5-chloroaniline (1) (10 g, 48.5 mmol) was dissolved in anhydrousdichloroethane (CH₂Cl₂, 250 mL) and sodium carbonate (Na₂CO₃, 11 g, 97mmol) was added thereto. The solution was cooled to 5° C. with ice waterunder nitrogen gas, and thiophosgene (5.5 mL, 72.7 mmol) was added veryslowly to the solution in that state. The reaction solution was stirredat room temperature for 12 hours and then filtered to remove inorganicmatter. After removing the solvent by distillation under reducedpressure, nucleic acid (n-Hexane, 50 mL) was added to the resultingsolid, and then the mixture was stirred for 10 minutes and subjected tofiltering to quantitatively obtain a title compound as a yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 7.51-7.49 (d, J=8.61 Hz, 1H), 7.26-7.25 (d,J=2.4 Hz, 1H), 7.13-7.09 (dd, J=2.46, 6.18 Hz, 1H).

LC/MS data: 249.52 g/mol

Synthesis of Ethyl(Z)-2-(((2-bromo-5-chlorophenyl)amino)(methylthio)methylene)-3-oxobutanoate,Compound 3a (C═C Bond Formation)

Isothiothianate (2) (10 g, 40 mmol) synthesized in step 1 was dissolvedin anhydrous DMF (20 mL), and the mixed solution was slowly added to asolution of ethyl oxobutanoate (5.2 g, 40 mmol) and K₂CO₃ (5.6 g, 40mmol) dissolved in DMF (100 mL) at room temperature. The mixture wasstirred for 12 hours at room temperature, and then iodomethane (5.7 g,40 mmol) was slowly added thereto at room temperature. The solution wasthen stirred at room temperature for one day. After completion of thereaction was confirmed by TLC, water and ethyl acetate were added andthe desired compound was extracted as an organic layer. Water wasremoved from the extracted organic layer using MgSO₄, and the extractedorganic layer was subjected to distillation under reduced pressure, andthen purification was performed using a column to obtain title Compound3a.

¹H NMR (300 MHz, CDCl₃) δ 12.90 (s, 1H), 7.45-7.42 (d, J=8.41 Hz, 1H),6.90-6.86 (d, J=7.74 Hz, 1H), 6.68 (s, 1H), 4.36-4.29 (m, 2H), 2.54 (s,3H), 2.04 (s, 3H), 1.37-1.33 (t, J=7.26 Hz, 3H).

LC/MS data: 393.69 g/mol

Synthesis of 3-acetyl-8-bromo-5-chloro-2-(methylthio)quinolin-4(1H)-one,Compound 4a (Cyclization)

Compound 3a synthesized in step 2 was dissolved in o-dichlorobenzene andstirred for 12 hours while heated at 180° C. After the reaction wascompleted, the reaction mixture was cooled to room temperature and wassubjected to distillation under reduced pressure. A nucleic acid wasadded to the resulting solid, and the mixture was stirred for 10 minutesand was subjected to filtering to obtain Compound 4a.

¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.91-7.88 (d, J=8.19 Hz, 1H),7.71-7.68 (d, J=8.49 Hz, 1H), 2.97 (s, 3H), 2.79 (s, 3H).

LC/MS data: 347.62 g/mol

Synthesis of3-acetyl-8-bromo-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one, Compound5a (Oxidation)

The quinolone compound 4a obtained in step 3 was oxidized with MCPBA(1.5 eq.) in anhydrous dichloroethane (CH₂Cl₂, 10 mL) to obtain titleCompound 5a.

¹H NMR (300 MHz, CDCl₃) δ 11.13 (s, 1H), 7.82-7.79 (d, J=8.43 Hz, 1H),7.38-7.36 (d, J=8.46 Hz, 1H), 3.02 (s, 3H), 2.78 (s, 3H).

LC/MS data: 363.62 g/mol

Synthesis of Ethyl(Z)-2-((benzylthio)((2-bromo-5-chlorophenyl)amino)methylene)-3-oxobutanoate,Compound 3b

Title Compound 3b was synthesized using benzyl bromide instead of MeI ina similar manner to the synthesis of Compound 3a.

¹H NMR (300 MHz, CDCl₃) δ 12.90 (s, 1H), 7.46-7.44 (m, 2H), 7.35-7.24(m, 4H), 6.91-6.89 (d, J=7.95 Hz, 1H), 6.70 (s, 1H), 4.49-4.19 (m, 4H),2.05 (s, 3H), 1.36-1.31 (t, J=7.11 Hz, 3H).

LC/MS data: 469.79 g/mol

Synthesis of 3-acetyl-2-(benzylthio)-8-bromo-5-chloroquinolin-4(1H)-one,Compound 4b

Title Compound 4b was synthesized in a similar manner to the synthesisof Compound 4a.

¹H NMR (300 MHz, CDCl₃) δ 8.59 (s, 1H), 7.93-7.90 (d, J=8.25 Hz, 1H),7.52-7.47 (m, 2H), 7.42-7.21 (m, 4H), 4.80 (s, 2H), 2.93 (s, 3H).

LC/MS data: 423.72 g/mol

Synthesis of3-acetyl-2-(benzylsulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one, Compound5b

Title Compound 5b was synthesized in a similar manner to the synthesisof Compound 5a.

Using the above-mentioned methods, the following compounds according tothe present disclosure were synthesized by modifying reactants and/orstarting materials appropriately. LC/MS and ¹H NMR measurement resultsare summarized in Table 4. In Table 4 below, MW refers to an averagemolecular weight, and MS is the value obtained by analyzing the actuallyprepared compounds.

TABLE 4 MW LC/ Compound (Molecular MS Number Formula Name Weight) data¹H NMR 1 3-acetyl-8-bromo-5-chloro-2- 362.62 363 ¹H NMR (300 MHz,CDCl₃)δ11.13 (methylsulfinyl)quinolin- (br, 1H), 7.81 (d, J = 8.4 Hz,1H), 7.37 4(1H)-one (d, J = 8.4 Hz, 1H), 3.02 (s, 3H), 2.78 (s, 3H). 23-acetyl-8-bromo-5-chloro-2- 346.63 348 ¹H NMR (300 MHz,(methylthio)quinolin-4(1H)- CDCl₃)δ8.67(s, 1H), 7.91-7.88(d, J = 8.19one Hz, 1H), 7.71-7.68(d, J = 8.49 Hz, 1H), 2.97(s, 3H), 2.79(s, 3H). 33-acetyl-2-(benzylthio)-8- 422.72 423 ¹H NMR (300 MHz, CDCl₃)δ16.43 (s,bromo-5-chloroquinolin- 0.5H), 8.59 (br, 0.5H), 7.91 (d, J = 8.34(1H)-one Hz, 1H), 7.62 (d, J = 8.4 Hz, 0.5H), 7.48-7.52 (m, 3H),7.27-7.43 (m, 5H), 7.22 (d, J = 8.4 Hz, 0.5H), 4.80 (s, 2H), 4.32 (s,1H), 2.93 (s, 3H), 2.69 (s, 1.5H). 4 3-acetyl-2-(benzylsulfinyl)- 438.72439 ¹H NMR (300 MHz, CDCl₃)δ10.24 8-bromo-5-chloroquinolin- (br, 1H),7.67 (d, J = 8.4 Hz, 1H), 7.29 4(1H)-one (d, J = 8.4 Hz, 1H), 7.13-7.22(m, 3H), 7.08-7.11 (m, 2H), 4.59-4.25 (m, 2H), 2.84 (s, 3H). 53-acetyl-8-bromo-5-chloro-1- 360.65 360 ¹H NMR (300 MHz, CDCl₃)δ7.92-methyl-2-(methylthio)quinolin- 7.89(d, J = 8.22 Hz, 1H), 7.36-7.33(d,4(1H)-one J = 8.13 Hz, 1H), 3.89(s, 3H), 2.74(s, 3H), 2.65(s, 3H). 63-acetyl-5, 8-dichloro-2- 318.17 318 ¹H NMR (300 MHz,(methylsulfinyl)quinolin- CDCl₃)δ11.07(s, 1H), 7.67- 4(1H)-one 7.64(d, J= 8.46 Hz, 1H), 7.44-7.41(d, J = 8.46 Hz, 1H), 3.02(s, 3H), 2.78(s, 3H).7 3-acetyl-6-fluoro-2-methyl-2- 265.30 266 ¹H NMR (300 MHz, CDCl₃)δ7.92-(methylthio)quinolin-4(1H)- 7.87(q, J = 5.1, 3.99 Hz, 1H), 7.69- one7.65(q, J = 2.88, 6.45 Hz, 1H), 7.48- 7.39(m, 1H), 4.53-4.46(q, J =7.14, 7.14 Hz, 2H), 4.08(s, 3H), 3.66(s, 3H), 1.48-1.44(t, J = 7.14 Hz,3H). 8 1-(6-fluoro-4-hydroxy-2- 251.28 252 ¹H NMR (300 MHz, CDCl₃)δ7.83-(methylthio)quinolin-3- 7.78(m, 2H), 7.49-7.42(m, 1H), 4.59-yl)ethan-1-one 4.52(q, J = 7.14 Hz, 2H), 2.58(s, 3H), 1.56-1.51(t, J =7.14 Hz, 3H). 9 3-acetyl-8-bromo-1-(4- 545.63 544 ¹H NMR (300 MHz,CDCl₃)δ8.09- bromobenzoyl)-5-chloro-2- 8.07(d, J = 5.73 Hz, 1H),8.06-8.04(d, (methylsulfinyl)quinolin- J = 6.15 Hz, 2H), 7.73-7.70(d, J= 8.58 4(1H)-one Hz, 2H), 7.56-7.54(d, J = 8.22 Hz, 1H), 3.15(s, 3H),2.63(s, 3H). 10 3-acetyl-8-bromo-5-chloro-2-((4- 457.16 456 ¹H NMR (300MHz, DMSO) δ 7.65- chlorobenzy1)thio)quinolin- 7.62(d, J = 8.13 Hz, 1H),7.45-7.42(d, 4(1H)-one J = 6.69 Hz, 2H), 7.29-7.26(d, J = 8.34 Hz, 2H),6.91-6.88(d, J = 8.19 Hz, 1H), 4.44(s, 2H), 2.40(s, 3H). 113-acetyl-8-bromo-5-chloro-2-((4- 473.16 472 ¹H NMR (300 MHz,chlorobenzyl)sulfinyl)quinolin- CDCl₃)δ10.21(s, 1H), 7.73- 4(1H)-one7.71(d, J = 8.43 Hz, 1H), 7.33-7.31(d, J = 8.37 Hz, 1H), 7.18-7.15(d, J= 9 Hz, 2H), 7.05-7.03(d, J = 8.25 Hz, 2H), 4.37(s, 2H), 2.84(s, 3H). 123-acetyl-8-bromo-5-chloro-2- 408.69 408 ¹H NMR (300 MHz, MeOD) δ 7.51-(phenylthio)quinolin-4(1H)- 7.48(m, 2H), 7.46-7.43(d, J = 8.11 Hz, one1H), 7.31-7.28(d, J = 7.71 Hz, 3H), 6.81-6.78(d, J = 8.19 Hz, 1H). 133-acetyl-8-bromo-5-chloro-2- 424.69 424 ¹H NMR (300 MHz, CDCl₃)δ7.84-(phenylsulfinyl)quinolin- 7.75(m, 2H), 7.68-7.64(m, 2H), 7.52- 4(1H)-one7.50(d, J = 8.43 Hz, 1H), 7.48-7.45(m, 1H), 7.38-7.35(d, J = 8.43 Hz,1H), 2.78(s, 3H). 14 3-acetyl-8-bromo-5-chloro-2-((2- 438.72 438 ¹H NMR(300 MHz, methoxyphenyl)thio)quinolin- CDCl₃)δ8.55(s, 1H), 7.709(m, 1H),7.633 4(1H)-one (m, 1H), 7.511(d, 1H, J = 8.43 Hz), 7.158(m, 3H),3.861(s, 3H), 2.781(s, 3H). 15 3-acetyl-8-bromo-5-chloro-2-((2- 454.72454 ¹H NMR (300 MHz, CDCl₃)δ7.84(d, J = methoxyphenyl)sulfinyl)quinolin-8.4 Hz, 1H), 7.383 (d, J = 8.4 Hz, 4(1H)-one 1H), 7.53 (m, 1H), 7.415(m, 1H), 6.949 (s, 1H), 6.956 (s, 1H), 3.86 (s, 3H), 2.634 (s, 3H) 163-acetyl-8-bromo-2-((4- 487.59 486 ¹H NMR (300 MHz, bromophenyl)thio)-5-CDCl₃)δ8.30(s, 1H), 7.779(d, J = 8.4 Hz, chloroquinolin-4(1H)-one 2H),7.614(d, J = 8.46 Hz, 2H), 7.541(d, J = 8.4 Hz, 1H), 7.183(d, J = 8.46Hz, 1H), 2.77(s, 3H). 17 3-acetyl-8-bromo-2-((4- 503.59 502 ¹H NMR (300MHz, bromophenyl)sulfinyl)-5- CDCl₃)δ11.37(s, 1H), 7.84-chloroquinolin-4(1H)-one 7.81(d, J = 8.46 Hz, 1H), 7.73-7.70(d, J = 8.73Hz, 2H), 7.60-7.57(d, J = 8.67 Hz, 2H), 7.39-7.38(d, J = 8.43 Hz, 1H),2.70(s, 3H). 18 1,1′-(8-bromo-5-chloro-2- 388.66 388 ¹H NMR (300 MHz,MeOD) δ 7.84 (d, (methylthio)-4-oxoquinoline- J = 8.25, 1H), 7.19(d, J =8.25, 1H), 1,3(4H)-diyl)bis(ethan-1-one) 2.72(s, dH), 2.57(s, 3H),2.18(s, 3H). 19 1,1′-(8-bromo-5-chloro-2- 404.66 404 ¹H NMR (300 MHz,(methylsulfinyl)-4- CDCl₃)δ8.07(m, 1H), 7.60(m, 1H),oxoquinoline-1,3(4H)- 3.03(s, 3H), 3.02(s, 3H), 2.78(s, 3H).diyl)bis(ethan-1-one) 20 3-acetyl-2-(benzylsulfinyl)-8- 621.72 620 ¹HNMR (300 MHz, (CD₃)₂CO)δ7.96- bromo-1-(4-bromobenzoyl)- 7.93(d, J = 8.22Hz, 1H), 7.73-7.60(m, 5-chloroquinolin-4(1H)-one 7H), 7.45-7.42(d, J =8.25 Hz, 2H), 7.16-7.13(d, J = 8.19 Hz, 1H), 2.86(s, 3H). 213-acetyl-8-bromo-1-(4- 561.63 560 ¹H NMR (300 MHz,bromobenzoyl)-5-chloro-2- CDCl₃)δ8.10(d, J = 8.22 Hz, 1H), 8.03-(methylsulfonyl)quinolin- 7.67 (dd, J = 8.61, 88.8 Hz, 4H), 4(1H)-one7.60(J = 8.22 Hz, 1H), 3.53(s, 3H), 2.67(s, 3H). 223-acetyl-8-bromo-5-chloro-1- 505.18 504 ¹H NMR (300 MHz, CDCl₃)δ7.42-(3-chloro-4-fluorobenzyl)-2- 7.37(m, 2H), 7.24-7.09(m, 3H), 4.49(s, 2H),3.44(s, 3H), (methylsulfinyl)quinolin- 2.14(s, 3H). 4(1H)-one 233-acetyl-2-(benzylthio)-8- 605.73 604 ¹H NMR (300 MHz, CDCl₃)δ8.06-bromo-1-(4-bromobenzoyl)- 8.03(d, J = 8.28 Hz, 1H), 7.93-7.91(d,5-chloroquinolin-4(1H)-one J = 8.64 Hz, 2H), 7.71-7.68(d, 8.64 Hz, 2H),7.54-7.51(d, J = 7.02 Hz, 2H), 7.49-7.46(d, J = 8.25 Hz, 1H), 7.30-7.27(d, J = 7.33 Hz, 2H), 6.97(s, 1H), 4.71(s, 2H). 243-acetyl-8-bromo-5-chloro-2- 374.68 374 ¹H NMR(300 MHz,(isopropylthio)quinolin- CDCl₃)δ16.32(s, 1H), 7.77- 4(1H)-one 7.86(d, J= 8.13 Hz, 1H), 7.26-7.23(d, J = 8.61 HZ, 1H), 4.54-4.45(m, 1H), 2.94(s,3H), 1.54-1.51(m, 6H). 25 3-acetyl-8-bromo-5-chloro-2- 390.68 390 ¹HNMR(300 MHz, (isopropylsulfinyl)quinolin- CDCl₃)δ10.99(s, 1H), 7.80-4(1H)-one 7.77(d, J = 8.37 Hz, 1H), 7.36-7.34(d, J = 8.4 Hz, 1H),3.61-3.51(m, 1H), 2.77(s, 3H), 1.63-1.61(d, J = 7.12 Hz, 3H),1.01-0.99(d, J = 6.78 Hz, 3H). 26 3-acetyl-8-bromo-5-chloro-2-((1-452.75 452 ¹H NMR(300 MHz, phenylethyl)sulfinyl)quinolin-CDCl₃)δ11.06(br, 1H), 7.82(d, J = 8.4 4(1H)-one Hz, 1H), 7.60-7.65 (m,2H), 7.41-7.50 (m, 3H), 7.38 (d, J = 8.5 Hz, 1H), 4.72 (q, J = 7.3 Hz,1H), 2.84 (s, 3H), 1.42 (d, J = 7.1 Hz, 3H). 27 3-(((3-acetyl-8-bromo-5-447.73 447 ¹H NMR(300 MHz, chloro-4-oxo-1,4- CDCl₃)δ7.92(d, J = 8.3 Hz,1H), 7.83 dihydroquinolin-2- (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.55yl)thio)methyl)benzonitrile (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.8 Hz,1H), 7.32 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 2.94 (s, 3H). 283-(((3-acetyl-8-bromo-5- 463.73 463 ¹H NMR (300 MHz, chloro-4-oxo-1,4-CDCl₃)δ10.27(br, 1H), 7.72(d, J = 8.5 dihydroquinolin-2- Hz, 1H),7.53-7.57 (m, 1H), 7.27-7.40 yl)sulfinyl)methyl)benzonitrile (m, 2H),4.59-4.22 (m, 2H), 2.85 (s, 3H). 29 3-acetyl-8-bromo-5-chloro-2- 474.70474 ¹H NMR (300 MHz, ((2,4-difluorobenzyl)sulfinyl)quinolin-CDCl₃)δ10.34(br, 1H), 7.74(d, J = 8.4 4(1H)-one Hz, 1H), 7.35 (d, J =8.4 Hz, 1H), 7.20- 7.28 (m, 1H), 6.81-6.87 (m, 1H), 6.60- 6.75 (m, 1H),4.53 (dd, J = 48.9, 13.2 Hz, 2H), 2.85 (s, 3H). 303-acetyl-8-bromo-5-chloro-2- 475.15 474 ¹H NMR (300 MHz, ((3-chloro-4-CDCl₃)δ7.92(d, J = 8.3 Hz, 1H), 7.83 fluorobenzyl)thio)quinolin- (s,1H), 7.76 (d, J = 7.9 Hz, 1H), 7.55 4(1H)-one (d, J = 7.7 Hz, 1H), 7.42(t, J = 7.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 2.94 (s,3H). 31 3-acetyl-8-bromo-5-chloro-2- 491.15 490 ¹H NMR (300 MHz,((3-chloro-4- CDCl₃)δ10.27(br, 1H), 7.73(d, J = 8.4fluorobenzyl)sulfinyl)quinolin- Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22-4(1H)-one 7.24 (m, 1H), 6.95-6.98 (m, 2H), 4.33 (q, J = 12.8 Hz, 2H),2.84 (s, 3H). 32 3-acetyl-8-bromo-5-chloro-2- 467.72 467 ¹H NMR (300MHz, ((4-nitrobenzyl)thio)quinolin- CDCl₃)δ8.16(d, J = 8.6 Hz, 2H), 7.924(1H)-one (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.32 (d, J =8.2 Hz, 1H), 4.90 (s, 2H), 2.94 (s, 3H). 333-acetyl-8-bromo-5-chloro-2-((4- 483.72 483 ¹H NMR (300 MHz,nitrobenzyl)sulfinyl)quinolin- CDCl₃)δ10.23(br, 1H), 8.08(d, J = 8.74(1H)-one Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.5, 3.9 Hz,3H), 4.49 (dd, J = 27.8, 12.6 Hz, 2H), 2.85 (s, 3H). 343-acetyl-2-(benzylsulfonyl)- 454.72 454 ¹H NMR(300 MHz,8-bromo-5-chloroquinolin- CDCl₃)δ10.25(s, 1H), 7.66(d, J = 8.464(1H)-one Hz, 1H), 7.28(d, J = 8.43 Hz, 1H), 7.20- 7.08(m, 5H), 4.41(d,J = 3, 2H), 2.84(s, 3H). 35 3-acetyl-8-bromo-5-chloro-1- 424.71 424 ¹HNMR(300 MHz, (methylsulfonyl)-2- CDCl₃)δ7.96(d, J = 8.25 Hz, 1H),(methylthio)quinolin-4(1H)- 7.42(d, J = 8.28 Hz, 1H), 3.30(s, 3H), one2.76(s, 3H), 2.73(s, 3H). 36 3-acetyl-8-bromo-5-chloro-2- 494.68 494 ¹HNMR (300 MHz, CDCl₃)δ8.08- (methylsulfinyl)-1- 8.05(d, J = 8.22 Hz, 1H),7.69-7.65(d, ((trifluoromethyl)sulfonyl)quinolin- J = 8.25 Hz, 1H),3.11(s, 3H), 2.78(s, 4(1H)-one 3H). 37 3-acetyl-8-bromo-5-chloro-1-521.22 520 ¹H NMR (300 MHz, CDCl₃)δ7.93- ((4-chlorophenyl)sulfonyl)-2-7.91(d, J = 8.22 Hz, 1H), 7.74-7.71(d, (methylthio)quinolin-4(1H)- J =8.7 Hz, 2H), 7.50-7.47(d, J = 8.61 one Hz, 2H), 7.32-7.30(d, J = 8.25Hz, 1H), 2.71(s, 3H), 2.62(s, 3H). 38 3-acetyl-8-bromo-5-chloro-2-531.78 531 ¹H NMR (300 MHz, CDCl₃)δ8.39- (methylthio)-l-((4- 8.36(d, J =8.85 Hz, 2H), 8.03-8.00(d, nitrophenyl)sulfonyl)quinolin- J = 8.85, 2H),7.96-9.93 (d, J = 8.22 Hz, 4(1H)-one 1H), 7.35-7.32(d, J = 8.22 Hz, 1H),2.74(s, 3H), 2.62(s, 3H). 39 3-acetyl-8-bromo-5-chloro-1- 454.73 454 ¹HNMR (300 MHz, CDCl₃)δ7.96- (ethylsulfonyl)-2- 7.93(d, J = 8.23 Hz, 1H),7.42-7.39(d, (methylsulfinyl)quinolin- J = 8.16 Hz, 1H), 3.54-3.46(q, J= 7.41, 4(1H)-one 7.5 Hz, 2H), 2.76(s, 3H), 2.73(s, 3H), 1.58-1.53(t, J= 7.38, 7.44, 3H). 40 3-acetyl-8-bromo-1-((4-(tert- 542.89 542 ¹H NMR(300 MHz, CDCl₃)δ7.88- butyl)phenyl)sulfonyl)-5- 7.85(d, J = 8.16 Hz,1H), 7.69-7.66(d, chloro-2-(methylthio)quinolin- J = 8.67 Hz, 2H),7.47-7.44(d, J = 8.7 4(1H)-one Hz, 2H), 7.25-7.23(d, J = 8.13 Hz, 1H),2.71(s, 3H), 2.63(s, 3H), 1.33 (s, 9H). 41 3-acetyl-8-bromo-1-((4-(tert-574.89 574 ¹H NMR (300 MHz, CDCl₃)δ8.10- butyl)phenyl)sulfonyl)-5-8.07(d, J = 8.22 Hz, 1H), 7.80-7.78(d,chloro-2-(methylsulfonyl)quinolin- J = 8.64 Hz, 2H), 7.62-7.59(d, J =8.25 4(1H)-one Hz, 1H), 7.58-7.55(d, J = 8.64 Hz, 2H), 3.48(s, 3H),2.71(s, 3H), 1.37(s, 9H). 42 3-acetyl-8-bromo-1-((4-(tert- 558.89 558 ¹HNMR (300 MHz, CDCl₃)δ8.05- butyl)phenyl)sulfonyl)-5- 8.03(d, J = 8.16Hz, 1H), 7.71-7.68(d, chloro-2-(methylsulfinyl)quinolin- J = 8.64 Hz,2H), 7.52-7.49(d, J = 8.28 4(1H)-one Hz, 3H), 3.13(s, 3H), 2.69(s, 3H),1.35(s, 9H). 43 3-acetyl-8-bromo-5-chloro-2- 491.61 490 ¹H NMR (300 MHz,DMSO) δ 7.93- ((2,5-dichlorobenzyl)thio)quinolin- 7.90(d, J = 8.25 Hz,1H), 7.84 (s, 1H), 4(1H)-one 7.52-7.49(d, J = 8.52 Hz, 1H), 7.37-7.33(m, 1H), 7.25-7.22(d, J = 8.34 Hz, 1H), 4.65(s, 2H). 443-acetyl-8-bromo-5-chloro-2- 507.60 506 ¹H NMR (300 MHz,((2,5-dichlorobenzyl)sulfinyl)quinolin- CDCl₃)δ10.35(s, 1H), 7.73-4(1H)-one 7.72(d, J = 10.86 Hz, 1H), 7.32(s, 2H), 7.17(s, 2H),4.81-4.49(dd, J = 13.33, 69.53 Hz, 2H), 2.81(s, 3H). 453-acetyl-8-bromo-5-chloro-2- 458.70 458 ¹H NMR (300 MHz, CDCl₃)δ7.93-((3,5-difluorobenzyl)thio)quinolin- 7.91(d, J = 8.28 Hz, 1H),7.33-7.30(d, 4(1H)-one J = 8.28 Hz, 1H), 7.06-7.04(m, 3H), 4.78(s, 2H),2.94(s, 3H). 46 3-acetyl-8-bromo-5-chloro-2- 474.70 474 ¹H NMR (300 MHz,((3,5-difluorobenzyl)sulfinyl)quinolin- CDCl₃)δ10.43(s, 1H),7.75-7.72(d, J = 4(1H)-one 8.4 Hz, 1H), 7.35-7.32(d. J = 8.46 Hz, 1H),6.80-6.68(m, 3H), 4.44-4.23(q, J = 12.63, 36.84 Hz, 2H), 2.84(s, 3H). 473-acetyl-8-bromo-5-chloro-2- 548.62 548 ¹H NMR (300 MHz, DMSO) δ 7.97-((3-iodobenzyl)thio)quinolin- 7.94(d, J = 5.55 Hz, 1H), 7.89(s, 1H),4(1H)-one 7.61-7.58(d, J = 8.16 Hz, 1H), 7.49- 7.46(d, J = 7.11 Hz, 1H),7.31-7.29(m, 1H), 7.13-7.80(t, J = 7.76 Hz, 1H), 4.55(s, 2H). 483-acetyl-8-bromo-5-chloro-2-((3- 564.62 564 ¹H NMR (300 MHz,iodobenzyl)sulfinyl)quinolin- CDCl₃)δ10.19(s, 1H), 7.74- 4(1H)-one7.71(d, J = 8.46 Hz, 1H), 7.56-7.54(d, J = 8.07 Hz, 1H), 7.39(s, 1H),7.35- 7.32(d, J = 8.46 Hz, 1H), 7.09-7.07(d, J = 8.01 Hz, 1H),6.97-6.92(t, J = 7.74 Hz, 1H), 4.40-4.30(q, J = 12.71, 6.06 Hz, 2H),2.87(s, 3H). 49 3-acetyl-8-bromo-5-chloro-2-((3- 440.71 440 ¹H NMR (300MHz, CDCl₃)δ7.93- fluorobenzyl)thio)quinolin- 7.91(d, J = 8.25 Hz, 1H),7.32-7.30(d, 4(1H)-one J = 8.19 Hz, 2H), 7.28-7.27(m, 2H), 6.97(s, 1H),4.79(s, 2H), 2.94(s, 3H). 50 3-acetyl-8-bromo-5-chloro-2- 456.71 456 ¹HNMR (300 MHz, ((3-fluorobenzyl)sulfinyl)quinolin- CDCl₃)δ10.30(s, 1H),7.70- 4(1H)-one 7.67(d, J = 8.56 Hz, 1H), 7.30-7.27(d, J = 8.43 Hz, 1H),7.15-7.07(m, 1H), 6.98-6.88(m, 2H), 6.83-6.81(d, J = 7.68 Hz, 1H),4.42-4.32(q, J = 12.66, 3.33 Hz, 2H), 2.82(s, 3H). 513-acetyl-8-bromo-5-chloro-2- 443.70 442 ¹H NMR (300 MHz,(((5-methylisoxazol-3- CDCl₃)δ10.50(br, 1H), 7.77(d, J = 8.4yl)methyl)sulfinyl)quinolin- Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.174(1H)-one (s, 1H), 4.33-4.67 (m, 2H), 2.83 (s, 3H), 2.39 (s, 3H). 52l-(2-(benzylthio)-8-bromo-5- 422.72 422 ¹H NMR (300 MHz,chloro-4-hydroxyquinolin-3- CDCl₃)δ7.82(d, J = 8.2 Hz, 1H), 7.53yl)ethan-1-one (d, J = 6.8 Hz, 2H), 7.32-7.48 (m, 3H), 7.26 (d, J = 8.4Hz, 1H), 6.77 (s, 2H), 5.24 (s, 3H). 53 l-(2-(benzylsulfinyl)-8- 438.72438 ¹H NMR (300 MHz, bromo-5-chloro-4- CDCl₃)δ7.99(d, J = 8.2 Hz, 1H),7.60 hydroxyquinolin-3-yl)ethan- (s, 1H), 7.54-7.57 (m, 2H), 7.51 (d, J= 1-one 8.2 Hz, 1H), 7.37-7.48 (m, 3H), 5.39 (s, 2H), 3.48(s, 3H). 54l-(2-(benzylsulfonyl)-8- 454.72 454 ¹H NMR (300 MHz, bromo-5-chloro-4-CDCl₃)δ7.94(d, J = 8.2 Hz, 1H), 7.73 hydroxyquinolin-3-yl)ethan- (s,1H), 7.54-7.58 (m, 2H), 7.45 (d, J = 1-one 8.1 Hz, 2H), 7.38-7.41 (m,2H), 5.42 (s, 2H), 3.01 (s, 3H). 55 3-acetyl-8-bromo-5-chloro-2-((3-468.75 468 ¹H NMR (300 MHz, methoxybenzyl)sulfinyl)quinolin-CDCl₃)δ10.32(s, 1H), 7.71-7.69(d, J = 8.4 4(1H)-one Hz, 1H),7.33-7.30(d, J = 8.43, 1H), 7.09-7.04(t, J = 7.8 Hz, 1H), 6.76- 6.70(m,2H), 6.65-6.63(d, J = 7.47 Hz, 1H), 4.44-4.34(q, J = 12.7, 4.86 Hz, 2H),3.70(s, 3H), 2.86(s, 3H). 56 3-acetyl-8-bromo-5-chloro-2-((4- 538.78 538¹H NMR (300 MHz, ((trifluoromethyl)thio)benzyl) CDCl₃)δ10.27(s, 1H),7.69- sulfinyl)quinolin-4(1H)-one 7.66(d, J = 8.40 Hz, 1H), 7.49-7.46(d,J = 8.01 Hz, 2H), 7.31-7.28(d, J = 8.40 Hz, 1H), 7.18-7.15(d, J = 8.16Hz, 2H), 4.52-4.37(q, J = 12.7, 17.1 Hz, 2H), 2.84(s, 3H). 573-acetyl-5,8-dichloro-2-((4- 439.26 439 ¹H NMR (300 MHz, MeOD) δ9.95(s,nitrobenzyl)sulfinyl)quinolin- 1H), 8.22-8.20(d, J = 8.6 Hz, 2H), 7.73-4(1H)-one 7.70(d, J = 8.31 Hz, 2H), 7.63-7.60(d, J = 8.22 Hz, 1H),7.29-7.26(d, J = 8.13 Hz, 1H), 4.59-4.10(q, J = 12.3, 122 Hz, 2H),2.72(s, 3H). 58 2-(((3-acetyl-8-bromo-5- 463.73 463 ¹H NMR (300 MHz,chloro-4-oxo-1,4- CDCl₃)δ10.30(br, 1H), 7.69(d, J = 8.4dihydroquinolin-2- Hz, 1H), 7.47-7.61 (m, 2H), 7.34-yl)sulfinyl)methyl)benzonitrile 7.45 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H),4.71 (q, J = 13.1 Hz, 2H), 2.85 (s, 3H). 593-acetyl-8-bromo-5-chloro-2-((3,5- 498.77 498 ¹H NMR (300 MHz,dimethoxybenzyl)sulfinyl)quinolin- CDCl₃)δ10.36(s, 1H), 7.69(d, J = 8.4Hz, 4(1H)-one 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.23 (s, 3H), 4.25-4.39 (m,2H), 3.62 (s, 6H), 2.83 (s, 3H). 60 3-acetyl-8-bromo-2-((4-(tert- 494.83494 ¹H NMR (300 MHz, butyl)benzyl)sulfinyl)-5- CDCl₃)δ10.15(br, 1H),7.62(d, J = 8.4 chloroquinolin-4(1H)-one Hz, 1H), 7.25 (d, J = 8.4 Hz,1H), 7.13 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 4.40 (dd, J =53.3, 12.7 Hz, 2H),, 2.83 (s, 3H), 1.11 (s, 9H). 613-acetyl-8-bromo-5-chloro-2- 376.65 376 ¹H NMR (300 MHz,((methoxymethyl)thio)quinolin- CDCl₃)δ10.62(br, 1H), 7.69(d, J = 8.44(1H)-one Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.07 (s, 2H), 3.66 (s, 3H),2.69 (s, 3H). 62 3-acetyl-8-bromo-5-chloro-2- 332.60 332 ¹H NMR (300MHz, mercaptoquinolin-4(1H)-one CDCl₃)δ10.11(br, 1H), 7.74(d, J = 8.5Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 3.15 (s, 3H). 63 3-acetyl-2-((4-542.83 542 ¹H NMR (300 MHz, benzoylbenzyl)sulfinyl)-8- CDCl₃)δ10.29(br,1H), 7.67(d, J = 8.4 bromo-5-chloroquinolin- Hz, 1H), 7.61 (d, J = 8.2Hz, 2H), 7.37- 4(1H)-one 7.59 (m, 5H), 7.31 (d, J = 8.4 Hz, 1H), 7.23(d, J = 8.2 Hz, 2H), 4.51 (q, J = 12.6 Hz, 2H), 2.85 (s, 3H). 643-acetyl-8-bromo-5-chloro-2-((4- 554.78 554 ¹H NMR (300 mhz,CDCl₃)δ10.30 ((trifluoromethyl)sulfinyl)ben- (br s, 1H), 7.70-7.62(m,3H), 7.41-7.26(m, yl)sulfinyl)quinolin-4(1H)-one 3H), 4.55-4.45(q, J =16.3 Hz, 2H), 2.84 (s, 3H). 65 2-((3-acetyl-8-bromo-5- 387.63 387 ¹H NMR(300 MHz, chloro-4-oxo-1,4- CDCl₃)δ10.97(br, 1H), 7.87(d, J = 8.4dihydroquinolin-2- Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 4.27yl)sulfinyl)acetonitrile (q, J = 16.3 Hz, 2H), 2.84 (s, 3H). 662-((3-acetyl-8-bromo-5- 371.63 371 ¹H NMR (300 MHz, chloro-4-oxo-1,4-CDCl₃)δ7.96(d, J = 8.3 Hz, 1H), 7.36 dihydroquinolin-2- (d, J = 8.3 Hz,1H), 4.30 (s, 2H), 2.94 yl)thio)acetonitrile (s, 3H). 67(Z)-3-((3-acetyl-8-bromo-5- 402.64 402 ¹H NMR (300 MHz, MeOD) δ9.03chloro-4-oxo-1,4- (br, 0.5H), 8.84 (br, 1H), 7.97 (d, J =dihydroquinolin-2- 8.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 0.5H),yl)thio)acrylic acid 7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.3 Hz,0.5H), 6.34 (d, J = 10.8 Hz, 0.5H), 6.22 (d, J = 10.3 Hz, 1H), 2.78 (s,3H), 2.72 (s, 1.5H). 68 3-acetyl-8-bromo-5-chloro-2- 564.76 564 ¹H NMR(300 MHz, CDCl₃)δ10.14 (s, ((4-(pentafluoro-16- 1H), 7.71 (d, J = 8.4Hz, 1H), 7.57 (d, sulfanyl)benzyl)sulfinyl)quinolin- J = 8.7 Hz, 2H),7.33 (d, J = 8.5 Hz, 4(1H)-one 1H), 7.20 (d, J = 8.3 Hz, 2H), 4.47 (dd,J = 30.2, 12.6 Hz, 2H), 2.87 (s, 3H). 69 3-acetyl-8-bromo-5-chloro-2-582.75 582 ¹H NMR (300 MHz, ((-fluoro-4-(pentafluoro-16- CDCl₃)δ10.19(s,1H), 7.71- sulfanyl)benzyl)sulfinyl)quinolin- 7.68(d, J = 8.43 Hz, 1H),7.33-7.30(d, 4(1H)-one J = 8.31 Hz, 1H), 4.73-4.40(q, J = 13.0, 72.1 Hz,2H), 2.83(s, 3H). 70 3-acetyl-8-bromo-5-chloro-2-((4- 506.72 506 ¹H NMR(300 MHz, CDCl₃)δ10.16 (s, (trifluoromethyl)benzyl)sulfinyl)quinolin-1H), 7.71 (d, J = 8.4 Hz, 1H), 7.46 (d, 4(1H)-one J = 8.1 Hz, 2H), 7.33(d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.60- 4.34 (m, 2H), 2.87(s, 3H). 71 3-acetyl-8-bromo-5-chloro-2-((4- 522.72 522 ¹H NMR (300 MHz,(trifluoromethoxy)benzyl)sulfinyl)quinolin- CDCl₃)δ10.24(br, 1H),7.69(d, J = 8.5 4(1H)-one Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.14 (d, J= 8.7 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 4.42 (q, J = 12.8 Hz, 2H), 2.84(s, 3H). 72 3-acetyl-8-bromo-5-chloro-2- 496.68 496 ¹H NMR (300 MHz,CDCl₃)δ10.34 (s, (((5-(trifluoromethyl)furan-2- 1H), 7.75 (d, J = 8.5Hz, 1H), 7.36 (d, yl)methyl)sulfinyl)quinolin- J = 8.4 Hz, 1H), 6.71 (s,1H), 6.59 (d, 4(1H)-one J = 3.1 Hz, 1H), 4.58 (dd, J = 71.0, 14.1 Hz,2H), 2.87 (s, 3H). 73 4-(((3-acetyl-8-bromo-5- 463.73 463 ¹H NMR (300MHz, CDCl₃)δ10.21(s, chloro-4-oxo-1,4- 1H), 775-7.72(d, J = 8.4 Hz, 1H),7.52- dihydroquinolin-2- 7.50(d, J = 8.04 Hz, 2H), 7.36-7.33(d,yl)sulfinyl)methyl)benzonitrile J = 8.43 Hz, 1H), 7.27-7.25(d, J = 8.1Hz, 2H), 4.50-4.39(q, J = 12.4, 6.33 Hz, 2H), 2.84(s, 3H). 743-acetyl-8-bromo-5-chloro-2- 491.15 491 ¹H NMR (300 MHz, ((2-chloro-6-CDCl₃)δ10.6(s, 1H), 7.75-7.72(d, J = 8.4 fluorobenzyl)sulfinyl)quinolin-Hz, 1H), 7.35-7.33(d, J = 8.4 Hz, 1H), 4(1H)-one 7.31-7.28(m, 1H),7.24-7.18(t, J = 8.8 Hz, 1H), 7.01-6.96(t, J = 8.0 Hz, 1H), 5.08-5.05(q,J = 1.9, 11, 120 Hz, 2H), 2.82(s, 3H). 75 3-acetyl-8-bromo-5-chloro-2-594.79 594 ¹H NMR (300 MHz, ((2-methoxy-4-(pentafluoro- CDCl₃)δ10.26(s,1H), 7.69- 16-sulfanyl)benzyl)sulfinyl)quinolin- 7.67(d, J = 8.40 Hz,1H), 7.31-7.28(d, 4(1H)-one J = 8.43 Hz, 1H), 4.80-4.40(q, J = 13.0,95.7 Hz, 2H), 2.82(s, 3H). 76 3-acetyl-8-bromo-5-chloro-2- 582.75 582 ¹HNMR (300 MHz, CDCl₃)δ10.13 (s, ((3-fluoro-5-(pentafluoro-16- 1H), 7.70(d, J = 8.5 Hz, 1H), 7.38 (s, sulfanyl)benzyl)sulfinyl)quinolin- 1H),7.33 (d, J = 8.6 Hz, 1H), 7.21 (d, 4(1H)-one J = 8.1 Hz, 1H), 7.09 (s,1H), 4.44 (s, 2H), 2.84 (s, 3H). 77 3-acetyl-8-bromo-5-chloro-2- 564.76564 ¹H NMR (300 MHz, CDCl₃)δ10.06 (s, ((3-(pentafluoro-16- 1H),7.59-7.68 (m, 2H), 7.29-7.38 sulfanyl)benzyl)sulfinyl)quinolin- (m, 4H),4.47 (q, J = 12.8 Hz, 2H), 4(1H)-one 2.85 (s, 3H). 783-acetyl-8-bromo-5-chloro-2- 528.67 528 ¹H NMR (300 MHz,(((perfluorophenyl)methyl)sulfinyl)quinolin- CDCl₃)δ10.48(s, 1H), 7.79-4(1H)-one 7.77(d, J = 8.43 Hz, 1H), 7.38-7.36(d, J = 8.31 Hz, 1H),4.49-4.40(q, J = 13.0, 128 Hz, 2H), 2.83(s, 3H). 79 3-acetyl-5,8-dichloro-2-((4- 494.32 494 ¹H NMR (300 MHz, CDCl₃)δ10.24(br((trifluoromethyl)thio)benzyl) s, 1H), 7.56-7.49 (m, 4H), 7.39-sulfinyl)quinolin-4(1H)-one 7.37(d, J = 8.52 Hz, 2H), 7.21-7.18(d, J =7.68 Hz, 2H), 4.52-4.40(q, J = 13.4 Hz, 2H), 2.87(s, 3H). 803-acetyl-5,8-difluoro-2-((4- 487.40 487 ¹H NMR (300 MHz, CDCl₃)δ9.78(br(pentafluoro-16- s, 1H), 7.59-7.58 (d, J = 8.49 Hz, 1H),sulfanyl)benzyl)sulfinyl)quinolin- 7.37-7.22(m, 3H), 7.06-6.98(m, 1H),4(1H)-one 4.41(s, 2H), 2.84(s, 3H). 81 3-acetyl-5,8-difluoro-2-(((5-419.32 419 ¹H NMR (300 MHz, CDCl₃)δ9.93(br (trifluoromethyl)furan-2- s,1H), 7.41-7.33(m, 1H), 7.08-7.00 yl)methyl)sulfinyl)quinolin- (m, 1H),6.71-6.69(m, 1H), 6.56- 4(1H)-one 6.55(m, 1H), 4.66(d, J = 14.1 Hz, 1H),4.48-4.44(d, J = 14.07 Hz, 1H), 2.83(s, 3H). 823-acetyl-5,8-difluoro-2-(((5- 366.34 366 ¹H NMR (300 MHz, CDCl₃)δ10.45(br methylisoxazol-3- s, 1H), 7.61-7.59(d, J = 8.49 Hz, 2H),yl)methyl)sulfinyl)quinolin- 7.41-7.38 (d, J = 8.46 Hz, 1H), 6.16(s,4(1H)-one 1H), 4.51-4.39(q, J = 13.5, 21.8 Hz, 2H), 2.81(s, 3H), 2.37(s,3H). 83 3-acetyl-5, 8-dichloro-2-((4- 520.16 520 ¹H NMR (300 MHz,CDCl₃)δ10.11(br iodobenzyl)sulfinyl)quinolin- s, 1H), 7.60-7.57(d, J =8.46 Hz, 1H), 4(1H)-one 7.51-7.49 (d, J = 8.22 Hz, 2H), 7.40- 7.37(d, J= 8.43 Hz, 1H), 6.83-6.81(d, J = 8.22 Hz, 2H), 4.32(s, 2H), 2.83(s, 3H).84 3-acetyl-8-bromo-5-chloro-2- 439.71 439 ¹H NMR (300 MHz, DMSO) δ8.41(d, ((pyridin-3-ylmethyl)sulfinyl)quinolin- J = 4.6 Hz, 1H), 8.21 (s,1H), 7.99 (d, 4(1H)-one J = 8.5 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.44(d, J = 8.5 Hz, 1H), 7.25 (dd, J = 7.6, 4.6 Hz, 1H), 4.71 (d, J = 13.1Hz, 1H), 4.37 (d, J = 13.0 Hz, 1H), 2.68 (s, 3H). 855,8-difluoro-3-isobutyryl-2-((4- 489.48 489 ¹H NMR (300 MHz,((trifluoromethyl)thio)benzyl) CDCl₃+ MeOD)δ7.60-6.92(m, 6H),sulfinyl)quinolin-4(1H)-one 4.45-4.41(m, 1H), 4.35-4.31(m, 1H),4.09-4.00 (m, 1H), 1.19-1.17(d, J = 6 Hz, 3H), 1.11-1.08(d, J = 7.17 Hz,3H). 86 5,8-dichloro-3-isobutyryl-2- 427.30 427 ¹H NMR (300 MHz,CDCl₃)δ10.43(br (((5-methylisoxazol-3- s, 1H), 7.59-7.56(d, J = 8.43 Hz,1H), yl)methyl)sulfinyl)quinolin- 7.38-7.35(d, J = 8.43 Hz, 1H), 6.13(s,4(1H)-one 1H), 4.50-4.39(d, J = 8.54 Hz, 2H), 4.14-4.05(m, 1H), 2.34(s,3H). 1.21- 1.15(dd, J = 6.8, 11.6 Hz, 6H). 873-benzoyl-5,8-difluoro-2-((4- 549.48 549 ¹H NMR (300 MHz, CDCl₃)δ7.74-(pentafluoro-16- 7.27(m, 10H), 7.00-6.92 (m, 1H),sulfanyl)benzyl)sulfinyl)quinolin- 4.80-4.76(d, J = 12.66 Hz, 1H), 4.53-4(1H)-one 4.49(d, J = 12.6 Hz, 1H). 88 3-benzoyl-5,8-dichloro-2- 461.31461 ¹H NMR (300 MHz, CDCl₃)δ7.77- (((5-methylisoxazol-3- 7.75(d, J =6.75 Hz, 2H), 7.74-7.70 (d, yl)methyl)sulfinyl)quinolin- J = 8.28 Hz,1H), 7.59-7.3 l(m, 5H), 4(1H)-one 6.18(s, 1H), 4.68(s, 2H), 3.10(s, 3H).89 methyl 5-(((3-acetyl-5,8- 442.26 442 ¹H NMR (300 MHz, CDCl₃)δ10.24(s, dichloro-4-oxo-1,4- 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.38 (d,dihydroquinolin-2- J = 8.5 Hz, 1H), 7.05 (d, J = 3.4 Hz,yl)sulfinyl)methyl)furan-2- 1H), 6.59 (d, J = 3.4 Hz, 1H), 4.65 (d,carboxylate J = 13.9 Hz, 1H), 4.44 (d, J = 13.9 Hz, 1H), 3.60 (s, 3H),2.85 (s, 3H). 90 2-(((3-acetyl-5, 8-dichloro-4- 463.29 463 ¹H NMR (300MHz, CDCl₃)δ10.52 (s, oxo-1,4-dihydroquinolin-2- 1H), 8.00-7.74 (m, 4H),7.62 (d, J = yl)sulfinyl)methyl)isoindoline- 8.4 Hz, 1H), 7.43 (d, J =8.5 Hz, 1H), 1,3-dione 5.74 (d, J = 12.6 Hz, 1H), 4.86 (d, J = 12.6 Hz,1H), 2.87 (s, 3H). 91 methyl 4-(((3-acetyl-5, 8- 452.30 452 ¹H NMR (300MHz, CDCl₃)δ10.23 (s, dichloro-4-oxo-1,4- 1H), 7.87 (d, J = 8.2 Hz, 2H),7.52 (d, dihydroquinolin-2- J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz,yl)sulfinyl)methyl)benzoate 1H), 7.23 (d, J = 8.2 Hz, 2H), 4.44 (q, J =12.5 Hz, 2H), 3.89 (d, J = 5.4 Hz, 3H), 2.85 (s, 3H). 923-acetyl-5-methoxy-2-((4- 465.45 465 ¹H NMR (300 MHz, CDCl₃)δ8.18 (d,(pentafluoro-16- J = 9.0 Hz, 1H), 7.71 (d, J = 8.7 Hz,sulfanyl)benzyl)thio)quinolin- 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.14 (d,4(1H)-one J = 2.4 Hz, 1H), 7.08 (dd, J = 9.0, 2.5 Hz, 1H), 4.70 (s, 2H),4.00 (s, 3H), 2.92 (s, 3H). 93 3-acetyl-5-methoxy-2-((4- 481.45 481 ¹HNMR (300 MHz, CDCl₃)δ9.63 (s, (pentafluoro-16- 1H), 8.28 (d, J = 9.0 Hz,1H), 7.57 (d, sulfanyl)benzyl)sulfinyl)quinolin- J = 8.6 Hz, 2H), 7.23(s, 1H), 7.04 (dd, 4(1H)-one J = 9.0, 2.2 Hz, 1H), 6.54 (d, J = 2.2 Hz,1H), 4.39 (dd, J = 36.0, 12.5 Hz, 2H), 3.87 (d, J = 10.5 Hz, 3H), 2.87(s, 3H). 94 3-acetyl-5-methoxy-2-(((5- 360.38 360 ¹H NMR (300 MHz,CDCl₃)δ10.43 (s, methylisoxazol-3- 1H), 8.34 (d, J = 9.0 Hz, 1H), 7.08(d, yl)methyl)sulfinyl)quinolin- J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.08 (s,4(1H)-one 1H), 4.45 (dd, J = 60.6, 13.3 Hz, 2H), 3.91 (s, 3H), 2.87 (s,3H), 2.32 (s, 3H). 95 8-bromo-5-chloro-3- 471.75 471 ¹H NMR (300 MHz,CDCl₃)δ10.49(br isobutyryl-2-(((5- s, 1H), 7.75-7.72 (d, J = 8.43 Hz,1H), methylisoxazol-3- 7.34-7.3 l(d, J = 8.37 Hz, 1H), 6.13(s,yl)methyl)sulfinyl)quinolin- 1H), 4.47(s, 2H), 4.16-4.07(m, 1H),4(1H)-one 2.35(s, 3H), 1.23-1.17(dd, J = 6.7, 12.0 Hz, 6H). 968-bromo-5-chloro-3- 469.73 469 ¹H NMR (300 MHz, CDCl₃)δ10.44(br(cyclopropanecarbonyl)-2- s, 1H), 7.75-7.72 (d, J = 8.43 Hz, 1H),(((5-methylisoxazol-3- 7.34-7.3 l(d, J = 8.4 Hz, 1H), 6.11(s,yl)methyl)sulfinyl)quinolin- 1H), 4.48-4.37(q, J = 10.5 Hz, 2H),4(1H)-one 3.70-3.62(m, 1H), 2.35(s, 3H), 1.28- 1.05(m, 4H). 975,8-dichloro-3- 425.28 425 ¹H NMR (300 MHz, CDCl₃)δ10.42(br(cyclopropanecarbonyl)-2- s, 1H), 7.61-7.58 (d, J = 8.43 Hz, 1H),(((5-methylisoxazol-3- 7.41-7.38(d, J = 8.43 Hz, 1H), 6.12(s,yl)methyl)sulfinyl)quinolin- 1H), 4.49-4.37(q, J = l 1.7 Hz, 2H),4(1H)-one 3.71-3.62(m, 1H), 2.36(s, 3H), 1.29- 1.06(m, 4H). 985-(((3-acetyl-8-bromo-5- 469.75 469 ¹H NMR (300 MHz, CDCl₃)δ10.31(brchloro-4-oxo-1,4- s, 1H), 7.79-7.77 (d, J = 8.43 Hz, 1H),dihydroquinolin-2- 7.42-7.36(m, 2H), 6.91-6.86(d, J = 3.84yl)sulfinyl)methyl)thiophene- Hz, 1H), 4.77-4.72(d, J = 13.74 , 1H),2-carbonitrile 4.63-4.59(d, J = 13.71, 1H), 2.86(s, 3H). 992-(((6-(1H-pyrazol-1- 505.77 505 ¹H NMR (300 MHz, DMSO- yl)pyridin-3-d₆)δ10.00(br s, 1H), 8.46-8.45 (s, 1H), yl)methyl)sulfinyl)-3-acetyl-8.1 l(s, 1H), 7.89-7.86(d, J = 8.46 Hz, 8-bromo-5-chloroquinolin- 1H),7.80(s, 1H), 7.79-7.71(m, 2H), 4(1H)-one 7.41-7.38(d, J = 8.37 Hz, 1H),6.55(s, 1H), 4.79-4.75(d, J = 12.99 Hz, 1H), 4.43-4.38(d, J = 13.08 Hz,1H), 2.70(s, 3H). 100 3-acetyl-2-(((6-aminopyridin- 454.72 454 ¹H NMR(300 MHz, DMSO-d₆)δ8.22- 3-yl)methyl)sulfinyl)-8- 7.65 (m, 4H),7.09-7.06(m, 1H), 4.36- bromo-5-chloroquinolin- 4.32(m, 1H),4.14-4.11(m, 1H), 2.88(s, 4(1H)-one 3H). 101 8-bromo-5-chloro-3- 564.82564 ¹H NMR (300 MHz, DMSO- (cyclopropanecarbonyl)-2-((4- d₆)δ10.11(br s,1H), 8.08-8.06 ((trifluoromethyl)thio)benzyl) (d, J = 8.43 Hz, 1H),7.55-7.52(d, J = sulfinyl)quinolin-4(1H)-one 7.71 Hz, 2H), 7.45-7.43(d,J = 8.37 Hz, 1H), 7.20-7.17(d, J = 7.71 Hz, 2H), 4.65-4.61(d, J = 12.66Hz, 1H), 4.42- 4.37(d, J = 12.87 Hz, 1H), 3.55-3.47(m, 1H), 1.28-1.02(m,4H). 102 3-acetyl-8-bromo-5-chloro-2- 521.73 521 ¹H NMR (300 MHz, DMSO-(((2-methyl-6- d₆)δ10.32(br s, 1H), 8.02-7.99(d,(trifluoromethyl)pyridin-3- J = 8.46 Hz, 1H), 7.68-7.65(d, J = 7.98yl)methyl)sulfinyl)quinolin- Hz, 1H), 7.55-7.52(d, J = 7.89 Hz, 1H),4(1H)-one 7.45-7.42(d, J = 8.49 Hz, 1H), 4.95- 4.91(d, J = 13.41 Hz,1H), 4.51- 4.46(d, J = 13.08 Hz, 2H), 2.68(s, 3H), 2.61(s, 3H). 103N-(4-(((3-acetyl-8-bromo-5- 531.82 531 ¹H NMR (300 MHz, DMSO-chloro-4-oxo-1,4- d₆)δ10.25(br s, 1H), 8.01 (m, 1H), dihydroquinolin-2-7.67-7.64(m, 1H), 7.41-6.98(m, 6H), yl)sulfinyl)methyl)phenyl)methane-4.79-4.50(m, 2H), 4.30-4.22(m, 2H), sulfonamide 2.81(s, 3H), 2.68(s,3H). 104 3-acetyl-8-bromo-5-chloro-2- 474.15 474 ¹H NMR (300 MHz,CDCl₃)δ10.20 (s, (((6-chloropyridin-3- 1H), 8.10 (s, 1H), 7.76 (d, J =8.4 Hz, yl)methyl)sulfinyl)quinolin- 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.36(d, 4(1H)-one J = 8.4 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.41 (dd, J =26.8, 13.0 Hz, 2H), 2.86 (s, 3H). 105 3-acetyl-8-bromo-5-chloro-2-512.80 512 ¹H NMR(300 MHz, CDCl₃) 6 12.59(((6-((2-methoxyethyl)amino)pyridin- (s, 1H), 7.75 (d, J = 8.2 Hz, 1H),7.63 (d, 3-yl)methyl)sulfinyl)quinolin- J = 7.6 Hz, 1H), 7.04 (d, J =8.2 Hz, 4(1H)-one 2H), 6.11 (d, J = 7.6 Hz, 1H), 4.61- 4.53 (m, 1H),3.90-3.84 (m, 1H), 3.71-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.41 (s, 3H),3.33 (s, 3H). 106 3-acetyl-8-bromo-5-chloro-2- 444.68 444 ¹H NMR (300MHz, DMSO-d₆)δ 7.76- (((4-methyl-1,2,5-oxadiazol- 7.73(d, J = 8.5 Hz,1H), 7.08-7.06(d, 3-yl)methyl)sulfinyl)quinolin- J = 8.5 Hz, 1H),4.52-4.48(d, J = 12.0 4(1H)-one Hz, 1H), 4.28-4.23 (d, J = 12.0 Hz, 1H),2.50(s, 3H), 2.44(s, 3H). 107 2-(((1H-pyrrolo[2,3- 478.75 478 ¹H NMR(300 MHz, DMSO- b]pyridin-5- d₆)δ11.62(br s, 1H), 8.00-7.32 (m,yl)methyl)sulfinyl)-3-acetyl- 5H), 6.38(s, 1H), 4.62-4.58(m, 1H),8-bromo-5-chloroquinolin- 4.20-4.10(m, 1H), 2.60(s, 3H). 4(1H)-one

Evaluation of Compounds of the Present Disclosure

Evaluation of Inhibitory Effect of Compounds on DNA Binding of c-Myc/Max

1. Protein Assay

1) Preparation of Recombinant c-Myc and Max Proteins

Recombinant proteins were prepared as described in the followingreferences: K. C. Jung et al., Fatty Acids, Inhibitors for the DNABinding of c-Myc/Max Dimer, Suppress Proliferation and Induce Apoptosisof Differentiated HL-60 Human Leukemia Cell, Leukemia, 2006, 20(1),122-7 or Kyung-Chae Jeong et al., Small-Molecule Inhibitors of c-MycTranscriptional Factor Suppress Proliferation and Induce Apoptosis ofPromyelocytic Leukemia Cell via Cell Cycle Arrest, Mol. BioSyst., 2010,6, 1503-1509.

2) Electrophoretic Mobility Shift Assay (EMSA)

The inhibitory activity of each candidate compound on DNA binding ofrecombinant c-Myc/Max was measured using an electrophoretic mobilityshift assay (EMSA). The ratio of protein-DNA complexes in each samplewas evaluated by measuring band intensity. The oligonucleotides (E-box)corresponding to the consensus binding site of Myc/Max were dimerizedthrough an annealing process. The protein mixture was incubated at roomtemperature for 5 minutes, and a DMSO solution containing each candidatecompound was added thereto. The mixture was further incubated for 5minutes, and the biotinylated DNA was added. To achieve a state ofequilibrium, the final mixture was incubated at room temperature for 10minutes. The protein-DNA complexes were separated from unbound free DNAby pre-electrophoresis using 8% polyacrylamide gel and 1×TBE buffer.After pre-electrophoresis, electrophoresis was performed at 120 V for 1hour in 1×TBE buffer. Each band was visualized using HRP-conjugatedstreptavidin and an ECL solution, and band intensity was measured usingimage analysis software.

2. Cell Based Assay

Commercially available bladder cancer cell lines were treated withtrypsin-EDTA and seeded in each well of a 96 well plate, followed byincubation for 24 hours. After incubation, candidate compounds wereadded to each well at a final concentration of 0 to 2 μM. Thecompound-treated cells were further incubated for 72 hours. Cellviability was measured using an ATP detection method (CellTiter-Glo®Luminescent Cell Viability Assay, Promega).

IC₅₀ values calculated from an in vitro assay and a proliferation assayusing compounds according to the present disclosure are summarized inTable 5 below.

TABLE 5 cell based assay Compound protein cell line 1 cell line 2 cellline 3 cell line 4 Number assay MBT-2 KU19-19 253J UM-UC-3 1 <1 μM 1.19μM 1.94 μM 1.35 μM 1.51 μM 2 <1 μM >2 μM >2 μM >2 μM >2 μM 3 <1 μM >2μM >2 μM >2 μM >2 μM 4 <1 μM 0.96 μM 1.05 μM 1.00 μM 1.33 μM 5 <1 μM >2μM >2 μM >2 μM >2 μM 6 <1 μM 1.44 μM >2 μM 1.22 μM 1.46 μM 7 <1 μM >2μM >2 μM >2 μM >2 μM 8 <1 μM >2 μM >2 μM >2 μM >2 μM 9 <1 μM 1.20 μM1.97 μM 1.10 μM 1.18 μM 10 <1 μM >2 μM >2 μM >2 μM >2 μM 11 <1 μM >2μM >2 μM 1.41 μM 1.49 μM 12 <1 μM >2 μM >2 μM >2 μM >2 μM 13 <1 μM >2μM >2 μM >2 μM >2 μM 14 <1 μM >2 μM >2 μM >2 μM >2 μM 15 <1 μM >2 μM1.91 μM >2 μM >2 μM 16 <1 μM >2 μM >2 μM >2 μM >2 μM 17 <1 μM >2 μM >2μM >2 μM >2 μM 18 <1 μM >2 μM >2 μM >2 μM >2 μM 19 <1 μM >2 μM >2 μM >2μM >2 μM 20 <1 μM >2 μM >2 μM >2 μM >2 μM 21 <1 μM >2 μM >2 μM >2 μM >2μM 22 <1 μM >2 μM >2 μM >2 μM >2 μM 23 <1 μM >2 μM >2 μM >2 μM >2 μM 24<1 μM >2 μM >2 μM >2 μM >2 μM 25 <1 μM >2 μM >2 μM >2 μM >2 μM 26 <1μM >2 μM >2 μM >2 μM >2 μM 27 <1 μM >2 μM >2 μM >2 μM >2 μM 28 <1 μM0.79 μM 1.46 μM 0.74 μM 0.79 μM 29 <1 μM 1.20 μM 1.68 μM 0.96 μM 1.13 μM30 <1 μM >2 μM >2 μM >2 μM >2 μM 31 <1 μM 1.28 μM 1.45 μM 0.89 μM 1.02μM 32 <1 μM >2 μM >2 μM >2 μM >2 μM 33 <1 μM 0.90 μM 1.42 μM 1.39 μM1.11 μM 34 <1 μM >2 μM >2 μM >2 μM >2 μM 35 <1 μM >2 μM >2 μM >2 μM >2μM 36 <1 μM 1.28 μM >2 μM >2 μM >2 μM 37 <1 μM >2 μM >2 μM >2 μM >2 μM38 <1 μM >2 μM >2 μM >2 μM >2 μM 39 <1 μM >2 μM >2 μM >2 μM >2 μM 40 <1μM >2 μM >2 μM >2 μM >2 μM 41 <1 μM >2 μM >2 μM >2 μM >2 μM 42 <1 μM >2μM >2 μM >2 μM 1.89 μM 43 <1 μM >2 μM >2 μM >2 μM >2 μM 44 <1 μM 1.15 μM1.27 μM 1.24 μM 0.97 μM 45 <1 μM >2 μM >2 μM >2 μM >2 μM 46 <1 μM 1.84μM 1.80 μM 1.96 μM 1.22 μM 47 <1 μM >2 μM >2 μM >2 μM >2 μM 48 <1 μM >2μM >2 μM >2 μM 1.82 μM 49 <1 μM >2 μM >2 μM >2 μM >2 μM 50 <1 μM 1.58 μM1.69 μM 1.43 μM 1.26 μM 51 <1 μM 0.76 μM 1.26 μM 1.13 μM 0.63 μM 52 <1μM >2 μM >2 μM >2 μM >2 μM 53 <1 μM >2 μM >2 μM >2 μM >2 μM 54 <1 μM >2μM >2 μM >2 μM >2 μM 55 <1 μM >2 μM 1.38 μM 1.33 μM 1.58 μM 56 <1 μM1.18 μM 0.94 μM 1.11 μM 1.25 μM 57 <1 μM >2 μM 1.83 μM 1.92 μM >2 μM 58<1 μM 0.86 μM 0.92 μM 0.92 μM 1.22 μM 59 <1 μM 1.30 μM 1.23 μM 1.14 μM1.37 μM 60 <1 μM >2 μM 1.56 μM 1.71 μM >2 μM 61 <1 μM >2 μM >2 μM >2μM >2 μM 62 <1 μM >2 μM >2 μM >2 μM >2 μM 63 <1 μM >2 μM >2 μM >2 μM >2μM 64 <1 μM 0.84 μM 1.41 μM 0.95 μM 1.06 μM 65 <1 μM >2 μM >2 μM >2μM >2 μM 66 <1 μM >2 μM >2 μM >2 μM >2 μM 67 <1 μM >2 μM >2 μM >2 μM >2μM 68 <1 μM 1.07 μM 1.25 μM 0.97 μM 1.11 μM 69 <1 μM 1.26 μM 1.50 μM1.08 μM 1.20 μM 70 <1 μM 1.33 μM 1.75 μM 1.04 μM 1.26 μM 71 <1 μM 1.47μM 1.60 μM 1.11 μM 1.61 μM 72 <1 μM 1.01 μM 1.37 μM 0.83 μM 0.82 μM 73<1 μM 1.00 μM 2.00 μM 1.34 μM 1.62 μM 74 <1 μM 1.15 μM 1.64 μM 0.81 μM1.54 μM 75 <1 μM 1.05 μM 1.21 μM 0.86 μM 1.01 μM 76 <1 μM 1.86 μM 1.86μM 1.24 μM 1.39 μM 77 <1 μM 1.45 μM 1.38 μM 0.90 μM 1.18 μM 78 <1 μM1.53 μM >2 μM 1.29 μM 1.39 μM 79 <1 μM >2 μM >2 μM >2 μM >2 μM 80 <1μM >2 μM >2 μM >2 μM >2 μM 81 <1 μM >2 μM >2 μM >2 μM >2 μM 82 <1 μM >2μM >2 μM >2 μM >2 μM 83 <1 μM 1.35 μM 1.60 μM 1.42 μM 1.31 μM 84 <1 μM0.67 μM 1.50 μM 0.87 μM 0.76 μM 85 <1 μM >2 μM >2 μM >2 μM >2 μM 86 <1μM 0.81 μM 1.41 μM 1.06 μM 1.26 μM 87 <1 μM >2 μM >2 μM >2 μM >2 μM 88<1 μM >2 μM >2 μM >2 μM >2 μM 89 <1 μM 1.27 μM >2 μM 1.84 μM 1.47 μM 90<1 μM >2 μM >2 μM >2 μM >2 μM 91 <1 μM 1.37 μM >2 μM >2 μM 1.56 μM 92 <1μM >2 μM >2 μM >2 μM >2 μM 93 <1 μM >2 μM >2 μM >2 μM >2 μM 94 <1 μM1.53 μM >2 μM >2 μM >2 μM 95 <1 μM 0.80 μM 1.29 μM 0.77 μM 1.06 μM 96 <1μM 1.06 μM >2 μM 1.49 μM 1.63 μM 97 <1 μM 0.81 μM 1.62 μM 1.20 μM 1.27μM 98 <1 μM 0.84 μM 1.90 μM 1.38 μM 1.52 μM 99 <1 μM 0.47 μM 1.12 μM0.80 μM 0.77 μM 100 <1 μM >2 μM >2 μM >2 μM >2 μM 101 <1 μM >2 μM >2 μM1.82 μM 1.93 μM 102 <1 μM 0.77 μM 1.58 μM 0.83 μM 1.07 μM 103 <1 μM >2μM >2 μM >2 μM >2 μM 104 <1 μM 0.71 μM 1.50 μM 0.87 μM 1.13 μM 105 <1μM >2 μM >2 μM >2 μM >2 μM 106 <1 μM >2 μM >2 μM >2 μM >2 μM 107 <1μM >2 μM >2 μM >2 μM >2 μM

As shown in Table 5, the compounds according to the present disclosurewere highly effective in inhibiting c-Myc/Max/DNA complex formation, andwere particularly effective in suppressing bladder cancer cell lines.

Evaluation of Selectivity of Compounds of the Present Disclosure

The selectivity of the compounds of the present disclosure to cancercells was evaluated in the same manner as described in “2. Cell basedassay”. As a comparative example, KSI-3716 compound of Formula 4, whichis a known compound, was used. Measurement results are summarized inTable 6 below.

TABLE 6 Compound Cytotoxicity (μM) Compd. MBT-2 KU19-19 UM-UC-3 253J RT4KSI-3716 1.0 0.4 0.9 1.2 1.5 Compound 4 1.0 1.1 1.5 1.1 >10 Compound 330.9 1.4 1.6 1.6 >10 253J: human urinary tract transitional cellcarcinoma

UM-UC-3: human urinary bladder transitional cell carcinoma

RT4: human urinary bladder transitional cell papilloma

As shown in Table 6, compound KSI-3716 causes nonselective cell death inboth benign (RT4) and malignant (253J and UM-UC-3) bladder cancer celllines, but the compounds of the present disclosure kill only malignantcancer cells with high selectivity.

The present disclosure provides novel compounds that can have variouspharmacological activities by inhibiting c-Myc/Max/DNA complexformation. The compounds according to the present disclosure orpharmaceutically acceptable salts thereof are excellent in safety andhas high selectivity in terms of inhibition of c-Myc/Max/DNA complexformation. Accordingly, various excellent effects can be exhibited.

All documents mentioned herein are incorporated herein by reference.When introducing elements of the present disclosure or the preferredembodiments thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising,” “including,” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements. Although the present disclosure is described with respect toparticular aspects, it should not be construed as limiting the detailsof these aspects.

1. A compound of Formula 1a or 1b, or a pharmaceutically acceptable saltthereof:

wherein, R_(1a) to R_(1d) are each independently hydrogen, a halogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₁₀ alkenyl, C₂₋₁₀ haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, ahydroxyl group, nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆alkylamino, alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,C₁₋₆ alkanoyl, C₃₋₇ cycloalkyl, an aryl, a heterocycle, or a heteroaryl,wherein R_(1a) to R_(1d) are each independently unsubstituted oroptionally substituted; R₂ is hydrogen, C₁₋₆ alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀ alkenyl carboxy, C₂₋₁₀haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxyl group, nitro,cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino, C₁₋₆ cyanoalkyl,alkyl)amino, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆alkanoyl, C₃₋₇ cycloalkyl, (C₁₋₆)alkyl(C₃₋₇)cycloalkyl, aryl,(C₁₋₆)alkylaryl, (C₁₋₆)haloalkylaryl,(C₂₋₆)alkenylamide(C₁₋₆)alkylalkoxy, a heterocycle,(C₁₋₆)alkylheterocycle, a heteroaryl, or (C₁₋₆)alkylheteroaryl, whereinR₂ is unsubstituted or optionally substituted; R₃ is C₁₋₄ alkyl,isoalkyl, cycloalkyl, phenyl, or C₁₋₄ haloalkyl; n is an integer from 0to 2; and Y is hydrogen, an alkyl, a haloalkyl, —C(O)alkyl, —C(O)aryl, asulfonylalkyl, a sulfonylaryl, an aryl, or an alkylaryl, wherein analkyl has 1 to 10 carbon atoms, and an aryl is unsubstituted oroptionally substituted, with the proviso that: i) a compound of Formula1a or 1 b having one or more of R_(1a) to R_(1d) being halogen, R₃ beingC₁₋₄ alkyl, isoalkyl, cycloalkyl, phenyl or C₁₋₄ haloalkyl, and R₂ beingC(R_(4a))(R_(4b))aryl wherein R_(4a) and R_(4b) being C₁₋₄ alkyl,halogen or C₁₋₄ cycloalkyl; and ii) a compound of Formula 1a or 1bhaving R_(1a) to R_(1c) being hydrogen, R_(1d) being fluorine, n being0, m being 1, Y being hydrogen, R₃ being C₁ alkyl, and R₂ being benzyl,are excluded.
 2. The compound of claim 1 having the structure of Formula2a or 2b, or a pharmaceutically acceptable salt thereof:

wherein, R_(1a) to R_(1d), R₃, n and Y are as defined for Formula 1a or1b in claim 1; m is an integer from 0 to 4; and R₆ is phenyl, oxazole,pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine, pyrimidine,furan, indole, benzopyrazole, benzothiazole, benzooxazole, isoxazole,benzoimidazole, 1,2,5-oxadiazole, pyrrolo[2,3-b]pyridine, orbenzothiophene, which is unsubstituted, or optionally substituted withone or more of hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and ahalogen, or is optionally substituted with one or more of hydrogen,phenyl, oxazole, pyrazole, pyrrole, imidazole, thiazole, thiophene,pyridine, pyrimidine, furan, indole, benzopyrazole, benzothiazole,benzooxazole, isoxazole, benzoimidazole, and benzothiophene, or isoptionally substituted with unsubstituted phenyl.
 3. The compound ofclaim 2, wherein one or more of R_(1a) to R_(1d) is a halogen, R₃ isC₁₋₄ alkyl, isoalkyl, cycloalkyl, phenyl, or C₁₋₄ haloalkyl, and m is 1or
 2. 4. The compound of claim 1 having the structure of Formula 3a or3b, or a pharmaceutically acceptable salt thereof:

wherein, R_(1a) to R_(1d), R₃, and n are the same as defined for Formula1a or 1b in claim 1; R_(4a) and R_(4b) are each independently hydrogen,a halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkyl in which one ormore hydrogens are substituted with a substituent other than halogen; Aris phenyl, a heteroaryl being 5-6-membered and having a heteroatomselected independently from N, S, and O, or a biheteroaryl being8-12-membered and having a heteroatom selected independently from N, S,and or O, wherein Ar is unsubstituted or optionally substituted with oneor more of a halogen, C₁₋₆ alkyl, C₁₋₆ alkylthio, C₁₋₆ haloalkyl, C₁₋₆haloalkylthio, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₁₀ alkenyl, C₂₋₁₀haloalkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ haloalkynyl, a hydroxyl group, COOH,nitro, cyano, C₁₋₆ alkoxycarbonyl, amino, C₁₋₆ alkylamino, alkyl)amino,amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkylamino, (C₁₋₆)alkylamino(C₁₋₆) alkylamino, C₁₋₆alkanoyl, SF₅, S(O)CF₃, SCF₃, NHC(═O)CH₃, C(═O)NHCH₃, NHSO₂CH₃, C₃₋₇cycloalkyl, an aryl, benzoyl, a heterocycle, a heteroaryl, phenyl,oxazole, pyrazole, pyrrole, imidazole, thiazole, thiophene, pyridine,pyrimidine, furan, indole, benzopyrazole, benzothiazole, benzooxazole,isoxazole, benzoimidazole, and benzothiophene, wherein the substituentof Ar is unsubstituted or optionally substituted with one or more ofCF3, a halogen, (C₁₋₃)alkyl, (C₁₋₃)haloalkyl, hydrogen, COOH, nitro,cyano, amino, di(C₁₋₃ alkyl)amino, NHC(═O)CH₃, and C(═O)NHCH₃. 5.(canceled)
 6. The compound according to claim 1, selected from the groupconsisting of:3-acetyl-8-bromo-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(methylthio)quinolin-4(1H)-one,3-acetyl-2-(benzylthio)-8-bromo-5-chloroquinolin-4(1H)-one,3-acetyl-2-(benzylsulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-1-methyl-2-(methylthio)quinolin-4(1H)-one,3-acetyl-5,8-dichloro-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-6-fluoro-1-methyl-2-(methylthio)quinolin-4(1H)-one,1-(6-fluoro-4-hydroxy-2-(methylthio)quinolin-3-yl)ethan-1-one,3-acetyl-8-bromo-1-(4-bromobenzoyl)-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-chlorobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-chlorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(phenylthio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(phenylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2-methoxyphenyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2-methoxyphenyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-2-((4-bromophenyl)thio)-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-2-((4-bromophenyl)sulfinyl)-5-chloroquinolin-4(1H)-one,1,1′-(8-bromo-5-chloro-2-(methylthio)-4-oxoquinoline-1,3(4H)-diyl)bis(ethan-1-one),1,1′-(8-bromo-5-chloro-2-(methylsulfinyl)-4-oxoquinoline-1,3(4H)-diyl)bis(ethan-1-one),3-acetyl-2-(benzylsulfinyl)-8-bromo-1-(4-bromobenzoyl)-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-1-(4-bromobenzoyl)-5-chloro-2-(methylsulfonyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-1-(3-chloro-4-fluorobenzyl)-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-2-(benzylthio)-8-bromo-1-(4-bromobenzoyl)-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(isopropylthio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(isopropylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((1-phenylethyl)sulfinyl)quinolin-4(1H)-one,3-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)methyl)benzonitrile,3-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile,3-acetyl-8-bromo-5-chloro-2-((2,4-difluorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-chloro-4-fluorobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-chloro-4-fluorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-nitrobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-nitrobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-2-(benzylsulfonyl)-8-bromo-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-1-(methylsulfonyl)-2-(methylthio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(methylsulfinyl)-1-((trifluoromethyl)sulfonyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-1-((4-chlorophenyl)sulfonyl)-2-(methylthio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(methylthio)-1-((4-nitrophenyl)sulfonyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-1-(ethylsulfonyl)-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-1-((4-(tert-butyl)phenyl)sulfonyl)-5-chloro-2-(methylthio)quinolin-4(1H)-one,3-acetyl-8-bromo-1-((4-(tert-butyl)phenyl)sulfonyl)-5-chloro-2-(methylsulfonyl)quinolin-4(1H)-one,3-acetyl-8-bromo-1-((4-(tert-butyl)phenyl)sulfonyl)-5-chloro-2-(methylsulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2,5-dichlorobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2,5-dichlorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3,5-difluorobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3,5-difluorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-iodobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-iodobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-fluorobenzyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-fluorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,1-(2-(benzylthio)-8-bromo-5-chloro-4-hydroxyquinolin-3-yl)ethan-1-one,1-(2-(benzylsulfinyl)-8-bromo-5-chloro-4-hydroxyquinolin-3-yl)ethan-1-one,1-(2-(benzylsulfonyl)-8-bromo-5-chloro-4-hydroxyquinolin-3-yl)ethan-1-one,3-acetyl-8-bromo-5-chloro-2-((3-methoxybenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-dichloro-2-((4-nitrobenzyl)sulfinyl)quinolin-4(1H)-one,2-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile,3-acetyl-8-bromo-5-chloro-2-((3,5-dimethoxybenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-2-((4-(tert-butyl)benzyl)sulfinyl)-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((methoxymethyl)thio)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-mercaptoquinolin-4(1H)-one,3-acetyl-2-((4-benzoylbenzyl)sulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-((trifluoromethyl)sulfinyl)benzyl)sulfinyl)quinolin-4(1H)-one,2-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)acetonitrile,2-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)acetonitrile,(Z)-3-((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)thio)acrylicacid,3-acetyl-8-bromo-5-chloro-2-((4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2-fluoro-4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-(trifluoromethyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((4-(trifluoromethoxy)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((5-(trifluoromethyl)furan-2-yl)methyl)sulfinyl)quinolin-4(1H)-one,4-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)benzonitrile,3-acetyl-8-bromo-5-chloro-2-((2-chloro-6-fluorobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((2-methoxy-4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-fluoro-5-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((3-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((perfluorophenyl)methyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-dichloro-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-difluoro-2-((4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-difluoro-2-(((5-(trifluoromethyl)furan-2-yl)methyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-difluoro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5,8-dichloro-2-((4-iodobenzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-((pyridin-3-ylmethyl)sulfinyl)quinolin-4(1H)-one,5,8-difluoro-3-isobutyryl-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin-4(1H)-one,5,8-dichloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,3-benzoyl-5,8-difluoro-2-((4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-benzoyl-5,8-dichloro-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,methyl5-(((3-acetyl-5,8-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)furan-2-carboxylate,2-(((3-acetyl-5,8-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)isoindoline-1,3-dione,methyl4-(((3-acetyl-5,8-dichloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)benzoate,3-acetyl-5-methoxy-2-((4-(pentafluoro-I6-sulfanyl)benzyl)thio)quinolin-4(1H)-one,3-acetyl-5-methoxy-2-((4-(pentafluoro-I6-sulfanyl)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-5-methoxy-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,8-bromo-5-chloro-3-isobutyryl-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,8-bromo-5-chloro-3-(cyclopropanecarbonyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,5,8-dichloro-3-(cyclopropanecarbonyl)-2-(((5-methylisoxazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,5-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)thiophene-2-carbonitrile,2-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)sulfinyl)-3-acetyl-8-bromo-5-chloroquinolin-4(1H)-one,3-acetyl-2-(((6-aminopyridin-3-yl)methyl)sulfinyl)-8-bromo-5-chloroquinolin-4(1H)-one,8-bromo-5-chloro-3-(cyclopropanecarbonyl)-2-((4-((trifluoromethyl)thio)benzyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,N-(4-(((3-acetyl-8-bromo-5-chloro-4-oxo-1,4-dihydroquinolin-2-yl)sulfinyl)methyl)phenyl)methanesulfonamide,3-acetyl-8-bromo-5-chloro-2-(((6-chloropyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((6-((2-methoxyethyl)amino)pyridin-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,3-acetyl-8-bromo-5-chloro-2-(((4-methyl-1,2,5-oxadiazol-3-yl)methyl)sulfinyl)quinolin-4(1H)-one,and2-(((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfinyl)-3-acetyl-8-bromo-5-chloroquinolin-4(1H)-one,or a pharmaceutically acceptable salt thereof.
 7. A compositioncomprising the compound of claim 1 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.